Pharmaceutical composition for nasal delivery

ABSTRACT

According to the invention, there is provided a solid pharmaceutical composition formulation for nasal delivery of an opioid antagonist, comprising a pharmacologically-effective amount of an opioid antagonist and a pharmaceutically-acceptable carrier. The compositions are preferably in the form of a powder produced by spray-drying, which are subsequently loaded into single use nasal applicators. Preferred pharmaceutically-acceptable carriers in this regard include disaccharides (e.g. lactose or trehalose) and dextrins (e.g. cyclodextrins or maltodextrins), preferably spray-dried together in combination. Compositions may further comprise an alkyl saccharide, preferably a sucrose ester, such as sucrose monolaurate. The compositions and applicators may be employed in the treatment of opioid overdose in subjects.

This application is a Continuation of U.S. patent application Ser. No.16/939,717, filed Jul. 27, 2020, which is a Continuation of U.S. patentapplication Ser. No. 16/876,468, filed May 18, 2020, now U.S. Pat. No.10,729,687, which is a Continuation-in-Part of U.S. patent applicationSer. No. 16/506,023, filed on Jul. 9, 2019, now U.S. Pat. No.10,653,690, which are hereby incorporated by reference in theirentirety.

This invention relates to new pharmaceutical compositions containingopioid antagonists that are useful in the treatment of inter aliaopioid/opiate overdose. The invention also relates to methods ofmanufacturing such compositions and formulating them into dosage forms,as well as their use in the treatment of opioid/opiate overdose.

PRIOR ART AND BACKGROUND

The listing or discussion of an apparently prior-published document inthis specification should not necessarily be taken as an acknowledgementthat the document is part of the state of the art or common generalknowledge.

Drug addiction is a worldwide problem, of which opioid dependence is amajor component. Opioids and opiates are highly addictive. People oftenstart using illegal opioids, such as heroin (diamorphine), forrecreational purposes, but this commonly leads to dependency.

That said, a new cohort of opioid-dependent individuals has begun toemerge in the last decade or so, particularly in the US, namelyso-called ‘white collar’ addicts, who have become dependent uponprescription opioids, typically initiated for the treatment of pain.

This occurs because of the increasingly extensive use of medicinalopioids as analgesics, in the treatment of moderate to severe, chroniccancer pain, as well as acute pain (e.g. during recovery from surgeryand breakthrough pain). Further, their use is increasing in themanagement of chronic, non-malignant pain.

People who become addicted to prescription opioids sometimes move on toillicit (‘street’) drugs, such as heroin. This may be because heroin ischeaper and (relatively speaking) easier to obtain than a prescriptionopioid.

It was estimated in 2010 that there were 15.5 million opioid-dependentpeople globally. Prevalence in Australasia, Western Europe, and NorthAmerica was higher than the global-pooled prevalence. According to theEuropean Monitoring Centre for Drugs and Drug Addiction Report in 2017,there were an estimated 1.3 million high-risk opioid users in Europe in2016. The opioid crisis has affected the US especially, and this hasescalated during recent years.

Thus, opioid dependence is a major health problem and long-term opioiduse is connected to a substantially increased risk of premature deathfrom drug overdoses, violence and suicide, as well as various other wellpublicized health issues, with an increasingly burgeoning socio-economicimpact in terms of cost of healthcare, lost productivity, addictiontreatment, and criminal activity (see Florence et al, Med. Care., 54,901 (2016)).

Opioid addicts typically feed their addiction by direct purchase ofopioids ‘on the street’, in the form of opioid-based powders (such asheroin). Heroin is usually mixed (or ‘cut’) with additives prior to saleby drug dealers, the amount and identity of which is almost alwaysunknown to the abuser. Furthermore, there is an increasing number ofaddicts being sold, and abusing, more potent opioids intended for thetreatment of e.g. pain, such as fentanyl and its analogues (see e.g.Prekupec et al, J. Addict. Med., 11, 256-265 (2017)).

Even without these additional issues, opioids are extremely dangerousdrugs if not delivered under medical supervision. As there are noquality controls on illicit drugs that are sold, particularly inrelation to the purity and strength issues discussed above, the wholeprocess is something of a ‘lottery’, which serves to add to the dangerand likelihood of overdose.

Overdose of opioids leads to depressed heart rate and breathing, leadingto hypoxia. Hypoxia not only leads to short- and long-term effects onthe central nervous system, including coma and permanent brain damage,but often leads to fatality. Overdoses of opioids, particularly heroinare very common. In 2015, drug overdoses accounted for 52,404 US deaths,of which 33,091 (63.1%) involved an opioid (see Rudd et al, MMWR, 65,1445 (2016)). It is not unheard of for people to overdose the very firsttime they use heroin.

A subject that has overdosed on an opioid requires urgent medicalattention. The only medicines that can be employed to treat opioidoverdoses effectively are opioid receptor antagonists, which act bybinding to opioid receptors, displacing opioid agonists (like heroin)without eliciting opioid effects of their own, whether intended (e.g.euphoria) or unintended and/or potentially dangerous (includingrespiratory depression). Emergency administration of opioid antagonistscan reduce (sometimes completely) the degree of opioid intoxication and,in essence, ‘reverse’ an opioid overdose.

Opioid antagonists are administered as intravenous solutions in Accidentand Emergency departments hospitals by medically-qualified staff.However, outside of the hospital environment, there are relatively fewtreatments available for the treatment of an opioid overdose (or asuspected overdose).

Two such treatments that are available commercially comprise the opioidantagonist, naloxone, delivered in the form of a single dose either as aliquid nasal spray (Narcan®; which is sprayed directly into onenostril), or as an auto-injector (Evzio®; which delivers drug byinjection into the muscle or under the skin). These treatments are oftenemployed by first responders (i.e. non-medically qualified personnel,such as ambulance crews, paramedics, police officers, family members,friends or other caregivers), buying time until more qualified medicalassistance is available.

These products are undoubtedly effective in helping to save lives.Naloxone and other opioid antagonists are highly water-soluble drugs,which enables the dissolution of an effective dose of e.g. naloxone in asmall quantity of liquid (100 μL) in a product like Narcan to treatopioid overdose. This enables it to act quickly in an emergencysituation.

However, in about one third of cases, Narcan is known to require two ormore doses in order to effect reversal of the overdose. Furthermore,Narcan has the disadvantage that it should not be allowed to freeze(otherwise it cannot be dispensed). This is a problem in cold climates,for example if the product is left inside a first responder's vehicleovernight.

Evzio, on the other hand, is a parenteral product that requires aneedle, presenting significant difficulties and/or problems for somefirst responders in what is an urgent situation.

Because of the huge increase in overdose deaths from opioid misuse,there is considerable demand for opioid overdose prevention medications,and also a clear clinical need for alternative and/or improvedmedications, in terms of their strength, onset and duration of action,as well as reproducibility and reliability in an emergency situation,which treating an opioid overdose undoubtedly is.

In addition to the commercial product, Narcan, liquid intranasal spraysare also disclosed in international patent application WO 2018/064672and US patent applications US 2018/0092839A and US 2019/0070105A.

Dry powder formulations comprising opioid antagonists that may beadministered by inhalation or intranasally are known from inter aliainternational patent applications WO 2010/142696 and WO 2019/038756, andUS patent application US 2018/0092839A.

Russo et al (J. Pharm. Sci., 95, 2253 (2006)) discloses spray-drying theopioid analgesic compound, morphine, with numerous excipients.Spray-dried formulations are also disclosed in Vengerovich et al.,Bulletin of Experimental Biology and Medicine, 163, 737 (2017), where itwas attempted to microencapsulate naloxone in various substances,including 2-hydroxypropyl-β-cyclodextrin, with a view to developingsustained-release preparations based on polymeric carriers for emergencycare.

Sugar esters are a class of natural and biodegradable non-ionicsurfactants consisting of a hydrophilic sugar ‘head group’ esterifiedwith fatty acids. The properties of sugar esters depend on the nature ofthe sugar and fatty acids used, and the degree of esterification of thesugar. They are made from natural products, sugar and edible fats, aretasteless, odourless and biodegradable, and are relatively nontoxic witha recommended acceptable daily intake of up to 30 mg/kg (joint FAO/WHOExpert Committee on Food Additives (JECFA)). Sugar esters, and inparticular sucrose esters, are widely used in the food and cosmeticsindustries but, thus far, are relatively underutilised in pharmaceuticalformulations (see, for example, the review article by Szüts andSzabó-Révész in Int. J. Pharm., 433, 1 (2012)).

Sucrose esters are known to be excellent oil-in-water-type emulsifiers.For example, emulsion-based compositions comprising sucrose esters aredescribed in international patent application WO 2005/065652. See alsointernational patent application WO 2003/061632.

Sucrose esters have also been employed to improve the bioavailability ofpoorly water-soluble drugs, such as ciclosporin in perorallyadministered dosage forms (see Hahn and Sucker, Pharm. Res., 6, 958(1989)). (It is to be noted that naloxone and other opioid antagonistsare highly water-soluble.)

Other peroral dosage forms comprising sucrose esters are described ininter alia international patent application WO 2016/016431.

International patent applications WO 2015/095389 and WO 2018/089709, andU.S. Pat. No. 9,895,444, also disclose that related compounds, sugarethers and in particular alkyl glycosides, can increase thebioavailability of opioid compounds in liquid nasal sprays. Sucroseesters are also mentioned in these documents. Similar drug deliveryvehicles are disclosed in US patent application US 2016/0045474.Furthermore, Kürti et al investigated the effect of sucrose esters onepithelial permeability in a culture model (see Toxicology in Vitro, 26,445 (2012)), and Li et al investigated the effect of varioussurfactants, including sucrose laurate, in in vivo absorption studies inrats, using sumatriptan as a model drug substance (see Drug Delivery,23, 2272 (2016)).

However, to the applicant's knowledge, there is no reported use ofsucrose esters in solid (e.g. powder) formulations intended forintranasal delivery.

We have now unexpectedly found that it is possible to formulate opioidantagonists in the form of dry powder compositions, that provide for asurprising and substantial improvement in bioavailability of opioidantagonist, as well as, even more surprisingly, an increase in the speedof absorption of opioid antagonist, compared to commercially-availableproducts. In particular, we have found that compositions that areproduced by a process of spray-drying with a specific combination ofcarrier materials as disclosed hereinafter, and/or similar dry powdercompositions that comprise an alkyl saccharide, such as a sucrose ester,are capable of giving rise to these unexpected effects.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagrammatic sectional view of a first suitable applicatorbased on the disclosure of U.S. Pat. No. 6,398,074, which isincorporated herein by reference. As shown, the applicator is configuredbefore actuation.

FIG. 2 is a sectional view of the applicator shown in FIG. 1 , but afteractuation.

FIG. 3 is a diagrammatic sectional view of a second suitable applicatorbased on the disclosure of U.S. Pat. No. 9,724,713, which isincorporated herein by reference. As shown, the applicator is configuredin the rest position.

FIG. 4 is a sectional view of the applicator shown in FIG. 3 , but nowconfigured in the actuation position.

FIG. 5 is a sectional view of the applicator shown in FIG. 3 , but nowconfigured in the dispensing position.

FIG. 6 is a sectional view of the applicator shown in FIG. 3 , but nowconfigured during return of the air expeller towards its rest position.

FIG. 7 is a diagrammatic perspective view of the air expeller of thedevice in FIGS. 3 to 6 shown in its rest position.

FIG. 8 is a graph showing permeation of naloxone through porcine nasaltissue in an ex vivo model.

FIG. 9 is a graph showing permeation of nalmefene through porcine nasaltissue in an ex vivo model.

FIGS. 10 and 11 show mean naloxone plasma concentrations versus time, bytreatment (linear scale), as obtained in a clinical trial, overdifferent time periods.

DISCLOSURE OF THE INVENTION

According to a first aspect of the invention, there is provided a solidpharmaceutical formulation/composition that is suitable for nasaldelivery of an opioid antagonist, comprising apharmacologically-effective amount of an opioid antagonist, and apharmaceutically-acceptable carrier material.

According to a second aspect of the invention, there is provided a solidpharmaceutical formulation/composition in the form of a powder that issuitable for nasal delivery of an opioid antagonist, comprising apharmacologically-effective amount of an opioid antagonist, optionallyan alkyl saccharide, and a pharmaceutically-acceptable carrier material.

Preferably, the powder is produced by a process of spray-drying.According to a third aspect of the invention, there is provided a solidpharmaceutical formulation/composition in the form of a spray-driedpowder that is suitable for nasal delivery of an opioid antagonist,comprising a pharmacologically-effective amount of an opioid antagonistand a pharmaceutically-acceptable carrier material, more preferably acarrier material that comprises a combination of at least twopharmaceutically-acceptable carrier materials, at least one of whichcarrier materials is a disaccharide and at least one of which carriermaterials is a dextrin.

Compositions of the first, second and third aspects of the invention arereferred to hereinafter together as ‘the compositions of the invention’.

The term ‘solid’ will be well understood by those skilled in the art toinclude any form of matter that retains its shape and density when notconfined, and/or in which molecules are generally compressed as tightlyas the repulsive forces among them will allow.

Opioid antagonists that may be employed in compositions of the inventioninclude any compound that has little to no opioid activity, but iscapable of displacement of an opioid agonist from an opioid receptor, soreversing or preventing the pharmacological effects of an opioidagonist, whether such effects are intended (euphoria, sedation and/orreduction in cravings), or unintended (unconsciousness, depressed heartrate, depressed lung function, hypoxia, etc.). In this respect, the term‘opioid agonists’ include exogenous opioid receptor ligands (i.e. thosementioned hereinbefore) and endogenous opioid receptor ligands (e.g.endorphins).

Opioid antagonists thus include naloxone, nalmefene and naltrexone, orpharmacologically-acceptable salts thereof. Preferred salts of thesecompounds include hydrochloride salts. Naloxone and nalmefene (and saltsof either) are particularly preferred.

In the context of the present invention, the term ‘opioid antagonists’may also include active pharmaceutical ingredients that are known to bepartial antagonists of opioid receptors, such as buprenorphine.Buprenorphine may be termed as a ‘partial antagonist of opioidreceptors’ because it is a partial agonist at the p-opioid receptor. Ithas high binding affinity, and competes with other agonists, such asmethadone, heroin and morphine, at the p-opioid receptor. Opioid agonisteffects of buprenorphine are less than the maximal effects of other,‘full’ opioid agonists, such as morphine, and are limited by a ‘ceiling’effect. The drug thus produces a lower degree of physical dependencethan other opioid agonists, such as heroin, morphine or methadone and istherefore used in substitution therapy. There is a reduced risk ofoverdose and reduced recreational value in opioid-tolerant subjects.Buprenorphine has been listed on the WHO's List of Essential Medicinesfor the treatment of opioid dependence. Displacement of full agonistsmay make buprenorphine useful in the context of the invention by beingcapable of reversing an opioid overdose, with a lower degree ofprecipitated withdrawal compared with full antagonists.

The amount of opioid antagonist that is employed in a composition of theinvention must be sufficient so as to antagonize the effect of theopioid receptor agonists (whether exogenous and/or endogenous),precipitate withdrawal symptoms and/or effect reversal of thepharmacological effects mentioned above. Pharmacologically-appropriateamounts of opioid antagonist (or salt thereof) may be determined by theskilled person and may vary with the type and severity of the conditionthat is to be treated, and what will be most suitable for an individualpatient. This is also likely to vary with the nature of the formulation,as well as the route of administration, the type and severity of thecondition that is to be treated, as well as the age, weight, sex, renalfunction, hepatic function and response of the particular patient to betreated.

The total amount of opioid antagonist that may be employed in acomposition of the invention will depend on the nature of the activecompound that is included, but may be in the range of from about 0.1%,such as about 1%, for example about 2% up to about 95%. For example, theamount of opioid antagonist may be from about 5%, such as about 10%(e.g. about 20%) to about 95%, such as about 75%, for example about 50%,e.g. about 40%, by weight based upon the total weight of thecomposition.

Appropriate doses of opioid antagonist (calculated as the freeacid/base) per unit dosage are in the range of about 1 mg to about 60 mg(e.g. about 40 mg), such as between about 2 mg and about 30 mg (e.g.about 20 mg, such as about 10 mg), depending on the opioid antagonistthat is employed.

Appropriate doses of naloxone (calculated as the free base) are in therange of about 1 mg to about 20 mg (e.g. about 15 mg), such as betweenabout 1.5 mg and about 10 mg, and may thus be about 1.8 mg, about 5.4mg, about 9.0 mg (e.g. about 10.8 mg), more preferably about 3.6 mg andespecially about 7.2 mg.

Appropriate doses of nalmefene (calculated as the free base) per unitdosage may be about 0.5 to about 10 mg, more preferably about 1 mg toabout 6 mg, including about 1.5 mg and, especially, about 3.0 mg.

Appropriate doses of naltrexone (calculated as the free base) per unitdosage form may be about 1 mg to about 20 mg (e.g. about 15 mg), morepreferably about 1.5 mg to about 10 mg.

In relation to either of the aforementioned aspects of the invention,appropriate pharmaceutically-acceptable carrier materials that may beemployed in compositions include any such relevant material that issuitable (and/or approved) for pharmaceutical use and/or for intranasaldelivery, and is capable of maintaining its physical and/or chemicalintegrity, and/or does not affect the physical and/or chemical integrityof the opioid antagonist and/or any other ingredients that may bepresent in the composition (such as alkyl saccharide), in the solidstate, under normal storage conditions.

The phrase ‘maintaining physical and chemical integrity’ essentiallymeans chemical stability and solid state stability.

By ‘chemical stability’, we include that any composition of theinvention may be stored in isolated solid form, or when loaded into anasal applicator or a reservoir therefor (with or without appropriatepharmaceutical packaging), under normal storage conditions, with aninsignificant degree of chemical degradation or decomposition.

By ‘solid state stability’, we include that any composition of theinvention may be stored in an isolated solid form, or when loaded into anasal applicator or a reservoir therefor (with or without appropriatepharmaceutical packaging), under normal storage conditions, with aninsignificant degree of solid state transformation (e.g.crystallisation, recrystallisation, loss of crystallinity, solid statephase transition (e.g. between a glassy or a rubbery state, or to anagglomerated form)), hydration, dehydration, solvatisation ordesolvatisation.

Examples of ‘normal storage conditions’ for compositions of theinvention, whether loaded into applicators, devices, drug reservoirs(such as canisters or containers) or otherwise, include temperatures ofbetween about −50° C. and about +80° C. (preferably between about −25°C. and about +75° C., such as about 50° C.), and/or pressures of betweenabout 0.1 and about 2 bars (preferably atmospheric pressure), and/orexposure to about 460 lux of UV/visible light, and/or relativehumidities of between about 5 and about 95% (preferably about 10 toabout 40%), for prolonged periods (i.e. greater than or equal to abouttwelve, such as about six months).

Under such conditions, compositions of the invention may be found to beless than about 15%, more preferably less than about 10%, and especiallyless than about 5%, chemically degraded/decomposed, and/or solid-statetransformed, as appropriate. The skilled person will appreciate that theabove-mentioned upper and lower limits for temperature and pressurerepresent extremes of normal storage conditions, and that certaincombinations of these extremes will not be experienced during normalstorage (e.g. a temperature of 50° C. and a pressure of 0.1 bar).

Such chemical and, particularly, physical stability is of criticalimportance in a solid state formulation, such as a powder, that is to beemployed in the treatment of e.g. an opioid overdose.

It is well known that significant difficulties may be experienced inattempting to obtain both chemically- and physically-stable solidcompositions, such as powders. In the present case, if the physical formof a composition of the invention changes under normal storageconditions (e.g. from a free flowing powder to an agglomerated mass thatis difficult to discharge), it will likely lead to non-reproducibilityof dose of opioid antagonist when dispensing a composition (or even thecomplete inability to dispense it) from, or via, a nasal applicator,which will put the subject's life at significant risk.

For certain compositions of the invention (e.g. powders), exposure toatmospheric water may result in compositions that are less solid-statestable. For example, exposure to certain (e.g. higher) relativehumidities may affect the physical form of the composition, for exampleby deliquescence, and/or by lowering glass transition temperatures ofcompositions, and/or individual components of the compositions, such ascarrier materials, or in another way.

Accordingly, compositions of the invention, and nasal applicatorsincluding them, are preferably packaged within containers thatsubstantially prevent the ingress of atmospheric water under the normalstorage conditions hereinbefore defined. Such containers may includepackaging materials such as heat-sealed aluminium pouches and/orthermoformed plastics.

When the composition includes an alkyl saccharide, appropriatepharmaceutically-acceptable solid carrier materials thus includecellulose and its derivatives, such as sodium carboxymethyl cellulose,ethyl cellulose, cellulose acetate, hydroxypropylmethyl cellulose(hypromellose, HPMC), hydroxyethyl cellulose (HEC), hydroxypropylcellulose (HPC), methyl cellulose (MC), ethyl hydroxyethyl cellulose,carboxymethyl cellulose (CMC), modified cellulose gum, microcrystallinecellulose and sodium carboxymethyl cellulose; starches, such as ricestarch, tapioca starch, wheat starch and, more particularly, corn starchand potato starch; starch derivatives, such as pregelatinized starch,carboxymethyl starch, as well as moderately cross-linked starch,modified starch and sodium starch glycolate; polysaccharides, includingdextrins, such as dextrin, cyclodextrins and linear or brancheddextrins, such as maltodextrins; powdered tragacanth; malt; gelatin;talc; waxy excipients, such as cocoa butter and suppository waxes;polyols, such as solid polyethylene glycols; sugars, sugar alcohols andsaccharides, such as mannitol, maltitol, xylitol, sorbitol, lactose,glucose, galactose, sucrose, sucralose, trehalose, maltose, isomalt anddextrose; acrylic polymers, such as carbomer and its derivatives;polyvinylpyrrolidone (povidone, PVP); crosslinked polyvinylpyrrolidone;polyethylene oxide (PEO); chitosan (poly-(D-glucosamine)); naturalpolymers such as gelatin, sodium alginate, pectin; scleroglucan; xanthangum; guar gum; poly co-(methylvinyl ether/maleic anhydride); andcroscarmellose (e.g. croscarmellose sodium). Hypromellose acetatesuccinate (HPMCAS), copovidone and polyvinyl alcohol (PVA, or PVOH) mayalso be mentioned. Mixtures of any of the foregoing may be employed.

Compositions according to the first aspect of the invention may thus becompressed into a single unit dosage form, granulated into a pellet or apill, but are preferably provided in the form of a dry, free-flowingpowder. Compositions of the second and third aspects of the inventionare provided in the form of a dry, free-flowing powder. In the contextof any aspect of the invention, by ‘dry’ we include essentially free ofwater and other liquid solvents, which includes that there is less thanabout 10%, such as less than about 5%, more preferably about 3%, such asless than about 2%, e.g. less than about 1% of the formulation is aliquid, such as water.

Compositions of the invention may thus be administered in the form of aplurality of particles, which particles may individually and/orcollectively consist of, and/or comprise, compositions of the invention.Compositions of the invention may be prepared in a form of a simplepowder mixtures, powder microspheres, coated powder microspheres, alyophilised liposomal dispersion, or a combination thereof.

Whether in the form of a powder or otherwise, amounts of carriermaterial(s) that may be employed in compositions of the invention aretypically in the range of about 5% to about 99.9%, including up to about99% (e.g. up to about 95% or about 90%), such as about 10% (e.g. about25%, including about 35%) to about 85%, including about 50% to about75%, by weight, based upon the total weight of the composition.

Furthermore, whether in the form of a powder or otherwise, compositionsof the invention may be prepared by standard techniques, and usingstandard equipment, known to the skilled person. In this respect, thecompositions of the invention may be combined with conventionalpharmaceutical additives and/or excipients used in the art for relevantpreparations, and incorporated into various kinds of pharmaceuticalpreparations using standard techniques (see, for example, Lachman et al,“The Theory and Practice of Industrial Pharmacy”, Lea & Febiger, 3^(rd)edition (1986); “Remington: The Science and Practice of Pharmacy”, Troy(ed.), University of the Sciences in Philadelphia, 21^(st) edition(2006); and/or “Aulton's Pharmaceutics: The Design and Manufacture ofMedicines”, Aulton and Taylor (eds.), Elsevier, 4^(th) edition, 2013).

Dry powders may be prepared by mixing the opioid antagonist along withthe pharmaceutically-acceptable carrier material and, if present, thealkyl saccharide, and any other ingredients that may be included.Appropriate techniques that may be employed include simple dry mixing,granulation (including dry granulation, wet granulation, meltgranulation, thermoplastic pelletising, spray granulation),extrusion/spheronisation or freeze-drying.

Dry granulation techniques are also well known to those skilled in theart and include any technique in which primary powder particles areaggregated under high pressure, including slugging and rollercompaction, for example as described hereinafter.

Wet granulation techniques are well known to those skilled in the artand include any technique involving the massing of a mix of dry primarypowder particles using a granulating fluid, which fluid comprises avolatile, inert solvent, such as water, ethanol or isopropanol, eitheralone or in combination, and optionally in the presence of a binder orbinding agent. The technique may involve forcing a wet mass through asieve to produce wet granules which are then dried, preferably to a losson drying of less than about 3% by weight.

Melt granulation will be known by those skilled in the art to includeany technique in which granules are obtained through the addition of amolten binder, or a solid binder which melts during the process (whichbinder materials may comprise the pharmaceutically acceptable carriermaterial). After granulation, the binder solidifies at room temperature.Thermoplastic pelletising will be known to be similar to meltgranulation, but in which plastic properties of the binder are employed.In both processes, the agglomerates (granules) obtained comprise amatrix structure.

Extrusion/spheronisation will be well known to those skilled in the artto include any process involving the dry mixing of ingredients, wetmassing along with a binder, extruding, spheronising the extrudate intospheroids of uniform size, and drying.

Spray granulation will be known by those skilled in the art to includeany technique involving the drying of liquids (solutions, suspensions,melts) while simultaneously building up granulates in a fluid bed. Theterm thus includes processes in which foreign seeds (germs) are providedupon which granules are built up, as well as those in which inherentseeds (germs) form in the fluid bed due to abrasion and/or fracture, inaddition to any spray coating granulation technique generally. Thesprayed liquid coats the germs and assists further agglomeration ofparticles. It is then dried to form granules in the form of a matrix.

The term ‘freeze drying’ includes lyophilisation or cryodesiccation, andany low temperature desolvatization (e.g. dehydration) process, in whichproduct is frozen, pressure is lowered, and the frozen solvent (e.g.water) is removed by sublimation.

However, we prefer that compositions of the invention are prepared by aprocess of spray-drying.

Spray-drying will be understood by the skilled person to include anymethod of producing a dry powder from a liquid, including a solution ora suspension (including a slurry) that involves rapid drying using hotgas to convert a stream of liquid into vaporized solvent and particlesof solid, which solid particles comprise the solute that was previouslydissolved in a solution, and/or particles that were previously suspendedin the evaporated liquid.

Appropriate spray-drying equipment includes some form of atomizationmeans, such as a spray nozzle, which disperses the liquid into a spraywith a relatively uniform droplet size. Such means may include any meansthat is capable of producing a dry, free-flowing powder, and may includehigh pressure swirl nozzles, rotary disks and/or atomizer wheels, highpressure single fluid nozzles, two-fluid nozzles and/or ultrasonicnozzles.

The spray-dryer may be a single effect or a multiple effect spray-dryer,and may comprise an integrated and/or an external vibrating fluidizedbed, a particle separator, and/or a collection means which may be a drumor a cyclone.

Spray-drying may be employed to produce compositions of the invention inthe form of powders and, in doing so, encapsulate substances in acarrier material, or produce an amorphous composite of activeingredient, carrier materials and other ingredients.

In this respect, compositions of the invention in the form of powders,particularly if produced by spray-drying, may be considered to comprisea plurality of particles, which particles are themselves‘mono-particulate’ in their nature. By ‘mono-particulate’, we includethat the particles comprise a homogeneous or a heterogeneous mixture, inwhich active ingredients are encapsulated in an amorphous state withincarrier materials in the presence of other ingredients (e.g. anamorphous composite of those things). In this respect, such compositionsof the invention do not comprise mixtures of two or more discrete,separate particles of different ingredients in the form of a mixture,such as an ordered, or interactive, mixture of smaller particles ofactive ingredients associated with larger, but separate and chemicallydistinct, particles of carrier substances, as is often the case forinhaled drug delivery compositions (see, for example Mehta, J. DrugDelivery, Art. ID 5635010, 1-19 (2018)).

Spray-dried compositions of the invention are thus preferably amorphousin their nature, which includes wholly amorphous and/or predominantlyamorphous (for example more than about 50% by weight, such as more thanabout 75% by weight, including more than about 80% by weight, such asmore than about 90% by weight, or 95% by weight, including more thanabout 99% by weight amorphous), and may give rise to pharmaceuticalproducts that show excellent shelf-life, in terms of both physical andchemical stability, when stored under normal storage conditions, ashereinbefore defined.

According to a further aspect of the invention, there is provided aprocess for the manufacturing of a composition of the invention (in theform of a dry powder), wherein said process comprises the steps of:

-   -   i) mixing together the opioid antagonist, the alkyl saccharide        (if present) and the pharmaceutically-acceptable carrier        material, in an appropriate volatile solvent,    -   ii) spray-drying the mixture from step i) to form a spray-dried        plurality of particles.

Preferred volatile solvents include water, or organic solvents, such aslower alkyl alcohols (e.g. ethanol), haloalkanes. Other solvents thatmay be mentioned include hydrocarbons (e.g. C₅₋₁₀ alkanes),dimethylformamide, dimethylsulfoxide, ethyl acetate, acetone, etc.Mixtures of any of the foregoing solvents may be employed.

We prefer that mixing together the opioid antagonist, the alkylsaccharide (if present) and the pharmaceutically-acceptable carriermaterial with the solvent results in a solution that can be spray-dried.

Particularly preferred pharmaceutically-acceptable carrier materialsthat may be employed to produce spray-dried compositions of theinvention (whether according to the first, the second or the thirdaspect of the invention), and which possess the desirablecharacteristics mentioned herein, include saccharides, more preferablydisaccharides, such as maltitol, trehalose, sucralose, sucrose, isomalt,maltose and, particularly, lactose (including β-D-lactose andα-D-lactose, especially α-D-lactose monohydrate); and/or polymers,including any polymeric materials mentioned hereinbefore as appropriatecarrier materials (such as sodium carboxymethyl cellulose, sodium starchglycolate, polyvinylpyrrolidone and, particularly, hydroxypropylmethylcellulose, and the like) and, particularly, polysaccharides, such asdextrins, including cyclodextrins (e.g. α-, β- and γ-cyclodextrins andderivatives thereof, such as, 2-hydroxypropyl-γ-cyclodextrin,sulfobutylether β-cyclodextrin sodium salt, randomly methylatedβ-cyclodextrin, branched β-cyclodextrin and the like and, particularly,2-hydroxypropyl-β-cyclodextrin); and linear or branched dextrins, suchas maltodextrins, which are classified by DE (dextrose equivalent),which can be between 3 and 20 (the higher the DE value, the shorter theglucose chains), especially maltodextrin with a DE of between 6 and 15,such as 8 and 12.

Also included within the scope of the invention are combinations of twoor more of the above-mentioned preferred materials.

It is preferred that a carrier material, whether a single carriermaterial or a combination of two or more carrier materials, is capableof giving rise to a spray-dried composition of the invention in the formof a powder, wherein the composition possesses a glass transitiontemperature (Tg) that:

-   -   (a) enables its production as a hard and/or brittle, ‘glassy’,        amorphous, powdered physical form, that can be easily loaded        into a nasal applicator, or a drug reservoir and/or container        within, or adjunct to, such an applicator, as described herein;        and    -   (b) is high enough that, after such an applicator or reservoir        is packaged as described herein, and thereafter subjected to a        high external temperature (e.g. up to about 50° C. to about 80°        C.), it remains in that glassy state, rather than being        transformed into a more viscous or rubbery state, and/or a        crystalline state.

Such extreme external temperatures are often experienced inside vehicles(e.g. of first responders) in warm and/or sunny climates, which vehicleswill frequently be parked for extended periods of time in full sun,where the resultant heat gain can be enormous. If the Tg of acomposition of the invention is low, the composition may transform afterexposure to such high temperatures to such a viscous/rubbery state, thiswill give rise to inefficient discharging of the composition from theapplicator or reservoir (and so too the dose of opioid antagonist) oncethe applicator is actuated.

In this respect, we prefer that the lowest measurable Tg of acomposition of the invention is at least about 40° C., such as at leastabout 50° C., such as at least about 55° C., including at least about60° C., when measured at a relative humidity of up to about 35%, such asup to about 30%, including up to about 25% (e.g. up to about 20%, suchas less than about 15%, e.g. less than about 10%). By ‘lowest measurableTg’, we include that the composition of the invention may compriseparticles that are heterogeneous in their nature. In particular, if morethan one carrier material is employed, particles may comprise discreteregions of carrier materials, or composite mixtures thereof, that maypossess individual and separate Tg values. It will be clear to theskilled person that the value of the lowest measurable Tg has a strongimpact on the physical stability of the composition.

When the carrier material comprises a combination of one or moredisaccharide (as hereinbefore defined) and one or more polymericingredients (as hereinbefore defined, but particularly so when thepolymer is a dextrin) relative amounts of those ingredients in thecombination can be tailored to ensure the required level of physicaland/or chemical stability of active ingredient whilst, at the same time,not lowering the Tg of the composition of the invention in such a mannerthat it affects its physical stability. We have found that a ratio ofbetween about 50:1 to about 1:50 of disaccharide:polymer (e.g. dextrin)by weight, based on the total weight of the composition, may workdepending on the active ingredient that is employed. Preferred ratiosare in the range of about 10:1 to about 1:40 (including up to about 1:30or up to about 1:20), for example between about 2:1 and about 1:10, morepreferably about 1:1 to about 1:8 of disaccharide:polymer (e.g. dextrin)by weight, based on the total weight of the composition.

In particular, and as described hereinafter, we have found thatcompositions of the invention, when fabricated by spray-drying and:

-   -   (i) employing a disaccharide as a carrier material give rise to        vastly improved chemical stability of the opioid antagonist when        compared to monosaccharides, such as mannitol. This is        surprising, because mannitol has been used previously in        physical mixtures together with opioid antagonists, such as        naloxone, with no stability issues whatsoever;    -   (ii) employing a dextrin, such as cyclodextrin or maltodextrin,        as a carrier material provide for significantly improved        physical stability when compared to other carrier materials.    -   (iii) However, employing such a dextrin gave rise to an        unexpected chemical instability of the opioid antagonist;    -   (iv) which chemical instability could be solved by spray-drying        the dextrin along with a disaccharide.

A particularly preferred combination of carrier materials thus includesa disaccharide, and especially trehalose and, more preferably, alactose, such as α-D-lactose monohydrate, and a dextrin, and especiallya cyclodextrin, such as 2-hydroxypropyl-β-cyclodextrin, or amaltodextrin, such as maltodextrin 12DE. We have found that such acombination of carrier materials can be spray-dried together along withan opioid antagonist and an alkyl saccharide in appropriate proportionsto produce a composition of the invention that possesses both thedesired physical and chemical stability under normal storage conditions,as hereinbefore defined.

We have found that an amount of between about 5% (particularly about10%) and about 30%, such as between about 15% and about 25%, e.g.between about 17% and about 24%, by weight based on the total weight ofthe composition, of disaccharide provides for the required level ofchemical stability of opioid antagonist, such as naloxone, whilst at thesame time not lowering the Tg of the composition of the invention insuch a manner that it affects physical stability. Appropriate amounts ofdextrin are accordingly in the range of about 30% up to about 90%, suchas up to about 85%, including up to about 80%, and especially up toabout 75%, such as between about 40% and about 70%, e.g. between about43% and 67%, by weight based on the total weight of the composition.

As described hereinafter, compositions of the invention have been foundto exhibit surprisingly good bioavailability, and highly surprisinglymore rapid absorption, which likely will result in a more rapid onset ofaction, compared to relevant reference products (e.g., in the case ofnaloxone, Narcan nasal spray).

This is highly unexpected for several reasons, including that:

-   -   (a) unlike compositions of the invention, which are solids, in        existing products, such as Narcan, opioid antagonist (in that        case naloxone) is presented in a pre-dissolved state, ready for        absorption; and    -   (b) in any event, naloxone, and other opioid antagonists        mentioned herein are known to be highly bioavailable drugs, with        a rapid onset of action, when administered via the nasal mucosa.        Accordingly, the compositions represent a therapeutic        improvement on something that is already highly bioavailable and        rapidly acting.

As is further described hereinafter, compositions of the invention thatinclude alkyl saccharides have also been found to exhibit surprisinglygood bioavailability and speed of absorption compared to correspondingcompositions that do not include alkyl saccharides, and/or includedifferent excipients that are known to act as surfactants. This is verysurprising given that, when tested ex vivo, such alkyl saccharidesshowed a tendency to decrease permeation of opioid antagonist, such asnaloxone, through mucosal membranes, whereas different surfactants,including some of those listed hereinafter, showed a tendency toincrease permeation.

Alkyl saccharides that may be employed in the compositions of theinvention include alkyl glycosides, which may be defined as any sugarjoined by a linkage to an alkyl group, such as a C₇₋₁₈ alkyl glycoside.Alkyl glycosides thus may include alkyl maltosides (such as dodecylmaltoside), alkyl glucosides, alkyl sucrosides, alkyl thiomaltosides,alkyl thioglucosides, alkyl thiosucroses and alkyl maltotriosides.However, we prefer that the alkyl saccharide is a sugar ester.

Sugar esters that may be used in the compositions of the inventioninclude trisaccharide esters, such as raffinose esters, monosaccharideesters, such as glucose esters, galactose esters and fructose esters,and/or, preferably, disaccharide esters, such as maltose esters, lactoseesters, trehalose esters and, in particular, one or more sucrose esters.

Sucrose esters that are employed in compositions of the invention have ahydrophilic-lipophilic balance value of between 6 and 20. The term‘hydrophilic-lipophilic balance’ (HLB) is a term of art that will bewell understood by those skilled in the art (see, for example, “The HLBSystem: A Time-Saving Guide to Emulsifier Selection”, published by ICIAmericas Inc, 1976 (revised 1980), in which document, Chapter 7 (pages20-21) provides a method of how to determine HLB values). The longer thefatty acid chains in the sucrose esters and the higher the degree ofesterification, the lower the HLB value. Preferred HLB values arebetween 10 and 20, more preferably between 12 and 20.

Sucrose esters thus include C₈₋₂₂ saturated or unsaturated fatty acidesters, preferably saturated fatty acid esters and preferably C₁₀₋₁₈fatty acid esters and most preferably C₁₂ fatty acid esters.Particularly suitable fatty acids from which such sucrose esters may beformed include erucic acid, behenic acid, oleic acid, stearic acid,palmitic acid, myristic acid and lauric acid. A particularly preferredsuch fatty acid is lauric acid. Commercially-available sucrose estersinclude those sold under the trademark Surfhope® and Ryoto®(Mitsubishi-Kagaku Foods Corporation, Japan).

Sucrose esters may be diesters or monoesters of fatty acids, preferablymonoesters, such as sucrose monolaurate. The skilled person willappreciate that the term ‘monolaurate’ refers to a mono-ester of lauricacid, and that the terms ‘lauric acid ester’ and ‘laurate’ have the samemeaning and can therefore be used interchangeably. Commerciallyavailable sucrose monolaurate products are also sometimes referred to as‘sucrose laurate’. Commercially-available sucrose monolaurate (orsucrose laurate) products, such as Surfhope® D-1216 (Mitsubishi-KagakuFoods Corporation, Japan), which may contain small amounts of diestersand/or higher sucrose esters, and minor amounts of other sucrose estersand free sucrose, are suitable for use in the invention. The skilledperson will understand that any reference to a specific sucrose esterherein includes commercially available products comprising that sucroseester as a principle component.

Preferred sucrose esters contain only one sucrose ester, which meansthat a single sucrose ester (e.g. a commercially-available sucrose esterproduct) contains a single sucrose ester as the/a principle component(commercially available products may contain impurities, for example amonoester product may contain small amounts of diesters and/or higheresters, such products may be considered to ‘contain only one sucroseester’ in the context of the present invention). As used herein, theterm ‘principle component’ will be understood to refer to the majorcomponent (e.g. greater than about 50%, such as about 70% weight/weightor volume/volume) in a mixture of sucrose esters, such as commoncommercially available surfactant products, which are typically soldwith a certain range of ester compositions.

A particularly preferred sucrose ester is sucrose monolaurate.

Amounts of alkyl saccharide in compositions of the invention are in therange of about 0.1% up to about 50%, more particularly up to about 10%,such as about 0.5% to about 5%, preferably about 0.75% to about 3% (e.g.to about 2%, such as about 1%), by weight, based upon the total weightof the composition.

In addition to any alkyl saccharide component that is included within acomposition of the invention, further, optional, additional excipientsmay be employed.

Such additional excipients may include one or more (further)surfactants. Surfactants that may be mentioned include polyoxyethyleneesters (e.g. Myrj™), including polyoxyl 8 stearate (Myrj™ S8), polyoxyl32 stearate (Gelucire® 48/16), polyoxyl 40 stearate (Myrj™ S40),polyoxyl 100 stearate (Myrj™ S100), and polyoxyl 15 hydroxystearate(Kolliphor® HS 15), polyoxyethylene alkyl ethers (e.g. Brij™), includingpolyoxyl cetostearyl ether (e.g. Brij™ CS12, CS20 and CS25), polyoxyllauryl ether (e.g. Brij™ L9 and L23), and polyoxyl stearyl ether (e.g.Brij™ S10 and S20), and polyoxylglycerides (e.g. Gelucire®), includinglauroyl polyoxylglycerides (Gelucire® 44/14) and stearoylpolyoxylglycerides (Gelucire® 50/13), sorbitan esters (e.g. Span™),including sorbitan monopalmitate (Span™ 40) and sorbitan monostearate(Span™ 60), polysorbates (Tweens™), including polysorbate 40(polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60(polyoxyethylene (20) sorbitan monostearate) and polysorbate 20(polyoxyethylene (20) sorbitan monolaurate), and sodium lauryl sulfate;and monoacyl glycerols (monoglycerides), such as 2-oleoylglycerol,2-arachidonoylglycerol, monolaurin, glycerol monomyristate, glycerolmonopalmitate, glyceryl hydroxystearate and, preferably, glycerolmonostearate, glycerol monooleate (e.g. Cithrol®) and glycerolmonocaprylate (e.g. Capmul®).

Other additional ingredients (excipients) that may be included incompositions of the invention include isotonicity and/or osmotic agents(e.g. sodium chloride), sterols (or steroid alcohols), such ascholesterol and phytosterols (e.g. campesterol, sitosterol, andstigmasterol); antioxidants (e.g. α-tocopherol, ascorbic acid, potassiumascorbate, sodium ascorbate, ascorbyl palmitate, butylatedhydroxytoluene, butylated hydroxyanisole, dodecyl gallate, octylgallate, propyl gallate, ethyl oleate, monothioglycerol, vitamin Epolyethylene glycol succinate, or thymol); chelating (complexing) agents(e.g. edetic acid (EDTA), citric acid, tartaric acid, malic acid, maltoland galactose); preservatives (e.g. benzyl alcohol, boric acid,parabens, propionic acid, phenol, cresol, or xylitol); viscositymodifying agents or gelling agents (such as cellulose derivatives,including hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, etc., starches and modifiedstarches, colloidal silicon dioxide, aluminium metasilicate,polycarbophils (e.g. Noveon®), carbomers (e.g. Carbopol®) andpolyvinylpyrrolidone); mucoadhesive polymers, such as carboxymethylcellulose, modified cellulose gum and sodium carboxymethyl cellulose(NaCMC); starch derivatives, such as moderately cross-linked starch,modified starch and sodium starch glycolate; crosslinked polyvinylpyrollidone, acrylic polymers, such as carbomer and its derivatives(Polycarbophyl, Carbopol®, etc.); polyethylene oxide (PEO); chitosan(poly-(D-glucosamine)); natural polymers such as gelatin, sodiumalginate, pectin; scleroglucan; xanthan gum; guar gum; polyco-(methylvinyl ether/maleic anhydride); and croscarmellose (e.g.croscarmellose sodium); pH buffering agents (e.g. citric acid, maleicacid, malic acid, or glycine); colouring agents; penetration enhancers(e.g. isopropyl myristate, isopropyl palmitate, pyrrolidone, ortricaprylin); other lipids (neutral and polar); and aromatic carboxylicacid, such as benzoic acid optionally substituted with one or moregroups selected from methyl, hydroxyl, amino, and/or nitro, forinstance, toluic acid or salicylic acid.

Total amounts of such ‘additional’ excipients (including surfactantsthat are not the one or more alkyl saccharide(s) that is/are (or may be)present in compositions of the invention) may be up to about 15% (e.g.about 10%), such as up to about 5%, by weight, based on the total weightof the composition.

The skilled person will appreciate that, if any additional optionalingredients are included within compositions of the invention, thenature of those ingredients, and/or the amounts of those ingredientsthat are included, should not have a detrimental effect on the Tg of thecomposition for the reasons described hereinbefore. In this respect,when compositions of the invention are made by spray-drying, suchoptional ingredients may be incorporated in the spray-drying process(i.e. mixed together along with the opioid antagonist, the optionalalkyl saccharide and the pharmaceutically-acceptable carrier material inthe appropriate volatile solvent and then spray-dried), or may beincluded separately to the spray-dried plurality of particles.

According to a further aspect of the invention, there is provided thecompositions of the invention for use in medicine (human andveterinary), and in particular in the treatment of substance (such asopioid, including opiate) overdose.

Overdose will be understood in the art to include what occurs whenlarger quantities of abusable substance, such as opioid, than may bephysically tolerated by an individual are taken, resulting in (in thecase of opioids) central nervous system and respiratory depression,hypoxia, miosis, and apnoea, one or more of which lead to death if nottreated rapidly (vide supra).

According to a further aspect of the invention there is provided amethod of treatment of substance (e.g. opioid) overdose, which method oftreatment comprises administration of a composition of the invention toa patient suffering from such a condition.

By ‘treatment’ of substance (e.g. opioid) overdose, we include theprophylaxis or the diagnosis of such overdose (i.e. if an overdose issuspected), in addition to therapeutic, symptomatic and palliativetreatment. This is because, by employing compositions of the inventionin the treatment of drug overdose, they may abrogate or prevent thedevelopment of the symptoms of opioid overdose mentioned hereinbefore.

Care should be taken when administering compositions of the inventioncomprising partial opioid antagonists, such as buprenorphine, with aview to ensuring that the patient has definitely overdosed on an opioid(and not, for example, on a benzodiazepine), and/or that the patient isphysically addicted to opioids.

Opioid antagonists may also be administered for use in the treatment ofconditions mediated by endogenous opioid agonists (e.g. endorphins),which conditions may be collectively classified together as‘endorphin-mediated hedonia’, as manifest by addictive behaviours (e.g.excessive eating (bulimia), drinking (alcoholism), exercise, sex,gambling, etc.).

Thus, according to a further aspect of the invention there is provided amethod of treatment of addiction and/or an addictive behaviour mediatedby activation of endogenous opioid agonists, such as endorphins(including bulimia, alcohol dependence, and addictions to exercise, sex,gambling, etc.), which method of treatment comprises administration of acomposition of the invention to patient suffering from, or susceptibleto, the relevant condition.

In the case of such addictions and addictive behaviours, by ‘treatment’,we include in particular the prophylaxis (prevention) and diagnosis ofsuch conditions, in addition to the palliative and, particularly, thesymptomatic treatment of such conditions.

Compositions of the invention may be administered intranasally by way ofany suitable intranasal dosing means that is known to the skilledperson, such as by way of a nasal applicator, or dispenser, means thatis capable of administering a suitable dose of opioid antagonist in theform of a composition of the invention to the nasal cavity.

Such an applicator means should thus be capable of housing, and storing,the composition of the invention itself, or capable of being attached toa reservoir/container that houses and stores the composition of theinvention, for example in the form of a powder, and do so without theconsequence of a significant loss of physical and chemical integrity ofthe composition, including by way of ingress of water. In this way, thecomposition will be usable as soon as the applicator device is actuatedby an end user, whereupon the applicator will deliver composition (e.g.powder) with an appropriate dose of opioid antagonist as defined hereinto the nasal mucosa of a subject.

Appropriate applicator means have been described in the prior art. Whenused with compositions of the invention (particularly those in the formof a powder), such compositions may be loaded into a reservoir that isattached to, or forms part of, such an applicator means, where it iscontained until the applicator means, or dispenser, is actuated.Hereinafter the terms ‘applicator’, ‘dispenser’, ‘device’ ‘applicatormeans’, ‘dispensing means’, ‘applicator device’ and ‘dispensing device’may be used interchangeably and mean the same thing.

Such applicator means may thus also include a mechanism for expellingthe powder formulation from the reservoir through an exit means, whichexit means includes anything sized for placement within a human nostril,such as an appropriately-shaped nozzle.

Thus, the applicator should be capable of providing a reproducible andsufficient amount of powder formulation in a single administration step(and in a manner in which the device does not require ‘priming’), thatwill provide a therapeutic dose of opioid antagonist.

Nasal applicators/inhalation devices that may be employed to administercompositions of the invention in the form of powders may includemultiple-dose applications, such as metered dose inhalation devices(MDIs), dry powder inhalation devices (DPIs; including low, medium andhigh resistant DPIs) and soft mist inhalation devices (SMIs) that may beadapted based on technology that is known in the field of delivery ofactive ingredients to the lung.

In MDIs, compositions of the invention should be capable of forming astable suspension when suspended in solvents that are typically employedtherein, such as a propellant, which propellant has a sufficient vapourpressure to form aerosols upon activation of the delivery device (e.g. ahydrocarbon, a fluorocarbon, a hydrogen-containing fluorocarbon, or amixture thereof).

However, we prefer that the nasal applicator is a single dose applicatorfrom which a composition is dispensed following actuation, and is thendisposed of after use.

In this respect, suitable applicator means or devices include thosedescribed in U.S. Pat. No. 6,398,074, 6,938,798 or 9,724,713, therelevant disclosures in all of which documents are incorporated hereinby reference. FIGS. 1 and 2 of the present application are based on FIG.1 and FIG. 2, respectively, of U.S. Pat. No. 6,398,074, and FIGS. 3 to 7are based on FIG. 19 to FIG. 23, respectively, of U.S. Pat. No.9,724,713. Both are illustrations of applicators that be may be employedto administer a composition of the invention intranasally.

In FIG. 1 , the device comprises an upper body/dispenser head 1incorporating an outlet channel 40 (i.e. part of the ‘exit means’ ashereinbefore described) and a gripping means 60 allowing the user toactuate the device. Inside the upper body/dispenser head 1 an element ismounted, designated in its assembly by reference number 2, thatincorporates a reservoir 10 and an air chamber 22 for the air blast 20.It is possible for this element 2 to be produced in one piece with thebody 1. A lower body 3 is also provided in order to be able to sliderelative to the upper body 1 and relative to the element 2, the userexerting a push force on the lower body to actuate the device.

The reservoir 10 contains a single dose of a composition of the presentinvention. The reservoir 10 has an air inlet 11 and a product outlet 15.A product retention device 12, comprising a grid that is permeable toair, is disposed in the air inlet 11 to keep the product in thereservoir 10 until the composition is dispensed. The product outlet 15is blocked, preferably in a sealed fashion, by a closing ball 16, whichis removed from its blocking position by the flow of air when theapplicator is actuated and the product is being dispensed.

When a user actuates the device, a pressure is exerted on the plunger 25in such a way that the piston 21 compresses the air 20 contained in thechamber 22. Since the grid 12 is permeable to air, the compression ofthe air in chamber 22 creates a blast of air that is transmitted to thereservoir 10 and consequently is applied to the closing ball 16 which isblocking the product outlet 15.

The dimensions of the closing ball 16 and its fixing at the reservoirproduct outlet 15 are such that the ball 16 is removed from its blockingposition, when a minimum predetermined pressure is created through thereservoir 10 by way of a blast of the air 20.

The pre-compression created by the closing ball 16 ensures that when itis removed from its blocking position, the energy accumulated in thehand of the user is such that the piston 21 integral with the plunger 25is propelled within the chamber 22 thereby creating a powerful blast ofair 20, that is to say an air flow suitable to finely spray the dose ofcomposition of the invention.

When this minimum pressure is reached, the ball is quickly moved towardsthe outlet channel 40 of the device and the flow of air 20 created bythe blast expels substantially all of the dose of composition of theinvention that is contained within the reservoir 10.

Preferably, the outlet channel 40 has a diameter greater than thediameter of the closing ball 16 in order to allow the dose of product tobe expelled through the outlet channel 40 by flowing around the ball 16.As shown in FIG. 2 , which represents the same device after actuation,the channel 40 comprises a means 41 of arresting or fixing the ball 16in order to prevent its expulsion out of the device when the product isbeing expelled.

A further embodiment that may be employed to administer compositions ofthe invention intranasally is provided in U.S. Pat. No. 9,724,713 atcolumn 7, line 50 to column 8, line 61 and FIGS. 19 to 23, which arereproduced as FIGS. 3 to 7 of the present application.

In this embodiment, the reservoir 10 is secured in the upperbody/dispenser head 1 which includes the dispenser outlet channel 40(i.e. part of the ‘exit means’ as hereinbefore described), which hasgripping means or finger rest 60, which allows the user to actuate thedevice. A radial shoulder 37 (see FIG. 5 ) of the upper body/dispenserhead 1 advantageously defines the assembled position of the reservoir 10in said of the upper body/dispenser head 1.

The mechanical opening system includes a set of rods 61, 62, wherein asecond rod portion 62 is pushed by said first rod portion 61 when thedevice is actuated. At the end of their actuation stroke, i.e. in thedispensing position, the set of rods 61, 62 co-operate with the closureelement 16, which is spherical, in particular a ball as in the firstembodiment discussed above, so as to expel it mechanically from itsclosed position.

In this embodiment, the piston 21 is separate from the first rod portion61, and slides both relative to the air chamber 22 and to a cylindricalsurface 614 that is secured to the first rod portion 61. FIG. 7 is adiagrammatic perspective view of the air expeller of the device in FIGS.3 to 6 , in its rest position.

The air chamber 22 may thus be cylindrical, and in its rest position isput into communication with the surrounding air at fluting or grooves615 that are formed in said cylindrical surface 614 and that co-operatewith the piston 21, in particular in its rest position. The piston 21thus includes an inner lip 215 that slides in airtight manner over thecylindrical wall 614 during actuation, and that co-operates with saidfluting 615 in its rest position. The piston 21 also includes an axialextension 216 that co-operates with a top edge 251 of the pusher element25 (termed a ‘plunger’ in the first embodiment) that moves said piston21 in the air chamber 22 during actuation.

A retainer member 42 is extended downwards by an axial extension 43 thatcomes into contact with the top axial end 610 of the first rod portion61 during actuation.

In addition, in this embodiment, there is no outer body, but merely acover 27 that is assembled on the bottom axial edge of the air chamber22.

A spring 80 is provided between the radial flange 225 of the air chamber22 and the part that forms the first rod portion 61 and the cylindricalsurface 614, so as to return the air expeller automatically into itsrest position after actuation.

The operating principle is as follows. In the rest position in FIG. 3 ,the reservoir 10 is closed in sealed manner by the retainer member 42and by the closure element/ball 16. The air expeller is open to theatmosphere by co-operation between the inner lip 215 of the piston 21and the fluting 615 of the cylindrical surface 614.

When it is desired to actuate the device, the user presses on the pusherelement 25. During this initial stroke, the inner lip 215 of the pistonleaves the fluting 615 so as to come to co-operate in airtight mannerwith the cylindrical surface 614, thereby closing the air chamber 22. Atthe same moment, the top edge 251 of the pusher element 25 comes intocontact with the axial extension 216 of the piston 21, and the top axialend 610 of the first rod portion 61 comes into contact with the axialextension 43 of the retainer member 42.

However, the top axial end 621 of the second rod portion 62 is still notin contact with the rounded surface 55 of the closure element/ball 16,as can be seen in FIG. 4 .

Continued actuation thus simultaneously moves the piston 21 in the airchamber, thereby compressing the air contained therein, and moves theretainer member 42 away from its position of closing the reservoir 10.When the second rod portion 62 contacts the rounded surface 55 of theclosure element/ball 16, said closure element/ball is expelledmechanically from its closed position, so as to enable the compositionto be expelled under the effect of the air compressed by the airexpeller.

The dispensing position is shown in FIG. 5 . As can be seen in FIG. 5 ,the retainer member 42 may become detached from the first rod portion 61while the composition is being expelled under the effect of thecompressed air provided by the air expeller. In this position, saidclosure element/ball is expelled out from the reservoir 10 so as toenable the fluid or powder to be dispensed under the effect of thecompressed air. The closure element/ball 16 thus becomes jammed insplines 3 of the upper body/dispenser head 1, which splines prevent inparticular any risk of said closure element/ball 16 being expelled outfrom said upper body dispenser head 1.

When the user relaxes the device, as shown in FIG. 6 , the spring 80that was compressed during actuation, returns the first rod portion 61towards its rest position. This creates suction that sucks the closureelement 16 and the retainer member 42 back towards, or close to, theirclosure positions. This thus blocks the path for new suction so as toavoid soiling the air expeller while it returns automatically into itsrest position, with the empty reservoir still assembled on the airexpeller. However, the piston 21 remains in its dispensing position as aresult of friction with the air chamber 22 and of the suction created inthe reservoir 30, such that the cylindrical surface 614 slides over theinner lip 215 of the piston until said inner lip co-operates once againwith the fluting 615. At this moment, the air chamber 22 is once againin communication with the surrounding air, and suction is no longercreated by the return into the rest position. The piston 21 is thus alsoentrained towards its rest position. This makes it possible to close thereservoir after use.

Optionally, the unit formed by the upper body/dispenser head 1 and theempty reservoir 10 could be removed from the air expeller and replacedby a new unit that includes a full reservoir.

Appropriate applicator devices that may be used include those availablefrom Aptar Pharma, France (UDS Monopowder). Other examples of applicatordevices that may be used in conjunction with compositions of theinvention (especially those in the form of powders) include thosedescribed in US patent application US 2011/0045088A, U.S. Pat. No.7,722,566 (see e.g. FIGS. 1 and 7 ) and U.S. Pat. No. 5,702,362 andinternational patent application WO 2014/004400, the relevantdisclosures of which documents are hereby incorporated by reference.

According to a further aspect of the invention, there is provided aprocess for the manufacturing of an applicator device comprising acomposition of the invention, wherein said process comprises the step ofloading said composition into a reservoir within or adjunct to saidapplicator device.

According to another aspect of the invention, there is provided anapplicator and/or dispenser device comprising a composition of theinvention in the form of a powder, suitable for dispensing that powder,which applicator/dispenser device comprises:

-   -   an outlet through which composition of the invention is        dispensed;    -   a means of externally generating a force (e.g. an air-flow) upon        actuation of the device by a user;    -   at least one (optionally replaceable) reservoir that contains a        composition of the invention, which reservoir is, or is capable        of being placed, in direct or indirect communication with the        dispenser outlet;    -   a displaceable sealing means in the device and/or the reservoir        for retaining the composition within the reservoir until the        composition is dispensed; and    -   a mechanical opening system that co-operates with said sealing        means such that the composition of the invention is expelled        mechanically by the forcing means when the device is actuated.

According to a still further aspect of the invention there is providedan applicator and/or dispenser device comprising a composition of theinvention in the form of a powder, suitable for dispensing that powder,which applicator/dispenser device comprises:

-   -   a dispenser outlet;    -   an air expeller for generating a flow of air while the device is        being actuated, said air expeller including a piston that slides        in an air chamber between a rest position and a dispensing        position;    -   said piston slides in airtight manner within said air chamber;    -   at least one reservoir that contains a dose of a composition of        the invention, said reservoir including an air inlet that is        connected to said air expeller;    -   a composition outlet that is connected to said dispenser outlet;    -   said air inlet including a displaceable sealing means (e.g. a        retainer member) for retaining the composition in the reservoir        until the composition is dispensed;    -   said composition outlet being closed by a closure element that        is fitted in the composition outlet of the reservoir;    -   said device further including a mechanical opening system that        co-operates with said closure element so as to expel it        mechanically from its closed position while the device is being        actuated; and    -   said piston of said air expeller, when in its rest position,        co-operating in non-airtight manner with said air chamber.

In the latter aspect of the invention, it is preferred that:

-   -   (i) the air chamber within which said piston slides in airtight        manner is substantially cylindrical;    -   (ii) the closure element is force fitted in the composition        outlet of the reservoir;    -   (iii) said air chamber is in communication with the atmosphere        in the rest position; and/or    -   (iv) said piston includes an inner lip that is suitable for        co-operating with a cylindrical surface, said cylindrical        surface includes fluting that co-operates in non-airtight manner        with said inner lip of the piston in its rest position.

Such an applicator or dispensing device is capable of providing for anappropriate and reproducible powder spray pattern and/or plume geometrythat enables efficient delivery of said powder to the nasal cavity (e.g.a nostril).

In compositions of the invention, mean particle sizes may be presentedas weight-, number-, or volume-, based mean diameters. As used herein,the term ‘weight based mean diameter’ will be understood by the skilledperson to include that the average particle size is characterised anddefined from a particle size distribution by weight, i.e. a distributionwhere the existing fraction (relative amount) in each size class isdefined as the weight fraction, as obtained by e.g. sieving (e.g. wetsieving). The term ‘volume based mean diameter’ is similar in itsmeaning to weight based mean diameter, but will be understood by theskilled person to include that the average particle size ischaracterised and defined from a particle size distribution by volume,i.e. a distribution where the existing fraction (relative amount) ineach size class is defined as the volume fraction, as measured by e.g.laser diffraction. As used herein, the term ‘number based mean diameter’will be understood by the skilled person to include that the averageparticle size is characterised and defined from a particle sizedistribution by number, i.e. a distribution where the existing fraction(relative amount) in each size class is defined as the number fraction,as measured by e.g. microscopy. Other instruments that are well known inthe field may be employed to measure particle size, such as equipmentsold by e.g. Malvern Instruments, Ltd (Worcestershire, UK), SympatecGmbH (Clausthal-Zellerfeld, Germany) and Shimadzu (Kyoto, Japan).

In the context of the present invention, the skilled person willunderstand that, to allow for intranasal administration, powders willtypically have a volume-based mean diameter (VMD) within the range ofabout 5 μm (e.g. about 10 μm) up to about 1,000 μm (e.g. up to about 500μm). Depending on the applicator device that is employed, the VMD may bein the range of about 10 μm to about 100 μm, such as about 20 μm toabout 60 μm.

Preferred particle size distributions may also include those in whichthe d10 is above about 3 μm and below about 75 μm (e.g. up to about 50μm), such as greater than about 10 μm, and the d90 is between about 80μm and about 1,000 μm (e.g. about 500 μm), such as less than about 100μm. The skilled person will understand that the parameter ‘d10’ (or‘Dv(10)’) means the size (or diameter) in a particle size distributionbelow which 10% of the total volume of material in the sample iscontained. Similarly, the ‘d90’ (or ‘Dv(90)’) means the size below which90% of the material is contained.

By powders having particle size diameters and/or VMDs within the aboveranges, we include the bulk VMD and/or the emitted VMD, that is theparticle size distribution when initially loaded into the device and/orwhen it is expelled therefrom, respectively.

Particle sizes may be measured by standard equipment, such as a dry (ora wet) particle size measurement technique, including dry dispersiontechnologies available from manufacturers, such as Sympatec and Malvern.

Preferred particle shapes include spherical or substantially spherical,by which we mean that the particles possess an aspect ratio smaller thanabout 20, more preferably less than about 10, such as less than about 4,and especially less than about 2, and/or may possess a variation inradii (measured from the centre of gravity to the particle surface) inat least about 90% of the particles that is no more than about 50% ofthe average value, such as no more than about 30% of that value, forexample no more than about 20% of that value.

Nevertheless, particles may be any shape, including irregular shaped(e.g. ‘raisin’-shaped), needle-shaped, disc-shaped or cuboid-shaped,particles. For a non-spherical particle, the size may be indicated asthe size of a corresponding spherical particle of e.g. the same weight,volume or surface area.

The spray angle of emitted (dispensed) powder composition of theinvention from an applicator and/or a dispenser device should preferablybe less than about 90°.

Compositions of the invention may be formulated with additional activeingredients, such as those known to treat opioid withdrawal symptoms,such as lofexidine, and/or partial opioid antagonists that are employedin the treatment of opioid dependence, for example, buprenorphine (videsupra).

Accordingly, co-administering at least one (preferably full) opioidantagonist as described hereinbefore alongside such an opioid withdrawalsymptom treatment (such as lofexidine or buprenorphine) may serve toabrogate the strong withdrawal symptoms that may be observed whenadministering a composition of the invention in the absence of such acompound.

Compositions of the invention may thus be provided along with a compoundthat is suitable for use in the treatment of opioid withdrawal symptoms(such as lofexidine or buprenorphine, or a pharmaceutically acceptable(e.g. HCl) salt of either compound, wherein the lattercompound/treatment is included within the composition (i.e. presented asa single pharmaceutical composition including both active ingredients).Alternatively, compositions of the invention may be co-administeredalong with a separate composition comprising a compound that is suitablefor use in the treatment of opioid withdrawal symptoms (such aslofexidine or buprenorphine) or a salt thereof.

Thus, there is further provided a pharmaceutical preparation comprisinga composition of the invention as hereinbefore defined, whichcomposition further includes a compound that is suitable for use in thetreatment of opioid withdrawal symptoms (such as lofexidine orbuprenorphine) or a pharmaceutically acceptable salt thereof, such apreparation is hereinafter referred to as a ‘combined preparation’.

There is further provided a process for the preparation of a combinedpreparation as hereinbefore defined, which process comprises bringinginto association an opioid antagonist as hereinbefore defined and acompound that is suitable for use in the treatment of opioid withdrawalsymptoms (e.g. lofexidine, buprenorphine or salt thereof) along with theother ingredients of a composition of the invention, and optionallyloading into a container that is for use within, or along with (e.g.attached to), an applicator device as hereinbefore described.

In such an instance, the combined preparation may have the same orsimilar physical attributes as those described hereinbefore forcompositions of the invention that do not include a compound suitablefor treatment of opioid withdrawal symptoms, in respect of which therelevant disclosures herein are incorporated by reference.

In a further aspect of the invention, there is also provided a kit ofparts comprising components (A) and (B) as follows:

-   -   (A) a composition of the invention; and    -   (B) a pharmaceutical composition including a compound that is        suitable for use in the treatment of opioid withdrawal symptoms        (e.g. lofexidine or buprenorphine) or a pharmaceutically        acceptable salt thereof in admixture with a        pharmaceutically-acceptable diluent or carrier,    -   wherein compositions (A) and (B) are optionally loaded, or are        presented for loading, into separate containers, which        containers are for use within, or along with (e.g. attached to),        the same, or separate, applicator devices that is/are suitable        for administration of compositions to the nasal cavity, e.g. as        hereinbefore described.

In such an instance, the pharmaceutical composition comprising opioidwithdrawal symptom treatment described under (B) above may have the sameor similar physical attributes as those described hereinbefore for acomposition of the invention, including that under (A) above. Forexample, the pharmaceutical composition comprising opioid withdrawalsymptom treatment may be presented in the form of a powder containingparticles with a similar particle size to those mentioned hereinbeforefor compositions of the invention.

According to a further aspect of the invention, there is provided amethod of making a kit of parts as defined above, which method comprisesbringing component (A), as defined above, into association with acomponent (B), as defined above, thus rendering the two componentssuitable for administration in conjunction with each other.

As alluded to above, by bringing the two components ‘into associationwith’ each other, we include that components (A) and (B) of the kit ofparts may be:

-   -   (i) provided as separate formulations (i.e. independently of one        another), which are subsequently brought together for use in        conjunction with each other in combination therapy; or    -   (ii) packaged and presented together as separate components of a        ‘combination pack’ for use in conjunction with each other in        combination therapy.

Thus, there is further provided a kit of parts comprising:

-   -   (I) one of components (A) and (B) as defined herein; together        with    -   (II) instructions to use that component in conjunction with the        other of the two components.

The kits of parts described herein may comprise more than oneformulation including an appropriate quantity/dose of opioidantagonist/salt, and/or more than one formulation including anappropriate quantity/dose of compound suitable for treatment of opioidwithdrawal symptoms, in order to provide for repeat dosing. If more thanone formulation (comprising either active compound) is present, suchformulations may be the same, or may be different in terms of the doseof either compound, chemical composition(s) and/or physical form(s).

With respect to the kits of parts as described herein, by‘administration in conjunction with’, we include that respectiveformulations comprising opioid antagonist (or salt thereof) and compoundsuitable for treatment of opioid withdrawal symptoms (or salt thereof)are administered, sequentially, separately and/or simultaneously, totreat the relevant condition.

Thus, in respect of the combination product according to the invention,the term ‘administration in conjunction with’ includes that the twocomponents of the combination product are administered (optionallyrepeatedly), either together, or sufficiently closely in time, to enablea beneficial effect for the patient, that is greater than if eitherformulation is administered (optionally repeatedly) alone, in theabsence of the other component. Determination of whether a combinationprovides a greater beneficial effect during treatment of a relevantcondition will depend upon the condition to be treated or prevented, butmay be achieved routinely by the skilled person.

After the emergency situation of treating acute opioid overdose has beendealt with, further compositions comprising compound suitable fortreatment of opioid withdrawal symptoms (e.g. lofexidine or, morepreferably, buprenorphine or salt thereof) may be administered asnecessary or desired. Such compositions may be similar in form tocompositions of the invention (and in respect of which the relevantdisclosures herein are incorporated by reference) or otherwise (e.g.sublingual formulations).

When the compound suitable for treatment of opioid withdrawal symptomsis buprenorphine, suitable doses may be in the range of between about 1mg to about 32 mg, more preferably about 5 mg to about 20 mg, calculatedas the free base.

When the compound suitable for treatment of opioid withdrawal symptomsis lofexidine, suitable doses (e.g. daily doses) may be in the range ofbetween about 0.1 mg to about 3 mg, such as about 0.5 mg to about 2 mg,calculated as the free base.

Wherever the word ‘about’ is employed herein in the context of amounts,for example absolute amounts, such as doses, weights, volumes, sizes,diameters, etc., or relative amounts of individual constituents in acomposition or a component of a composition (including concentrationsand ratios), timeframes, and parameters, such as temperatures, pressure,relative humidities, etc., it will be appreciated that such variablesare approximate and as such may vary by ±10%, for example ±5% andpreferably ±2% (e.g. ±1%) from the actual numbers specified herein. Thisis the case even if such numbers are presented as percentages in thefirst place (for example ‘about 10%’ may mean±10% about the number 10,which is anything between 9% and 11%).

Compositions of the invention have the advantage that they are capableof being stored over a wider range of temperatures than prior artcompositions, including those that are commercially-available (e.g., inthe case of naloxone, Narcan). Thus, compositions of the invention maybe subject to low temperatures (e.g. below freezing) without impactingthe amount of opioid antagonist that is administered to a subject.Further, compositions of the invention may have the advantage that theyare more physically and chemically stable at higher temperature thansuch prior art compositions.

Compositions of the invention further have the significant advantagethat they provide for higher bioavailability of opioid antagonistcompared to prior art compositions, including those that arecommercially-available (e.g., in the case of naloxone, Narcan). Thecompositions of the invention provide for this higher bioavailabilityalongside a more rapid absorption, which will likely lead to a morerapid onset of action than such prior art and/or commercially-availablecompositions, and thus meets a significant and serious medical need.

The compositions, pharmaceutical formulations, uses and methodsdescribed herein may also have the advantage that, in the treatment ofthe conditions mentioned hereinbefore, they may be more convenient forthe first responder, physician and/or patient than, be more efficaciousthan, be less toxic than, have a broader range of activity than, be morepotent than, produce fewer side effects than, have a lower inter-patientvariability, or that it/they may have other useful pharmacologicalproperties over, similar formulations or methods (treatments) known inthe prior art, whether for use in the treatment of opioid overdose (orof bulimia or alcohol dependence), or otherwise.

The invention is illustrated but in no way limited by way of thefollowing examples, with reference to the attached figures, in which:FIGS. 1 to 7 represent drawings of actuator devices that may be used todispense compositions of the invention, FIGS. 8 and 9 show permeation ofnaloxone, and nalmefene, respectively, through porcine nasal tissue inan ex vivo model; and FIGS. 10 and 11 show mean naloxone plasmaconcentrations versus time, by treatment (linear scale), as obtained ina clinical trial, over different time periods.

Example 1 Spray-Drying Opioid Antagonists with Various Saccharides

Naloxone HCl dihydrate (1.199 g; Johnson Matthey, UK) or nalmefene HCl(0.600 g; Santa Cruz Biotechnology Inc., USA) and naltrexone HCl (0.600g, Mallinckrodt Inc., USA) were separately mixed, along with differentsaccharides (5.088 g for naloxone and 2.554 g for nalmefene andnaltrexone), which were employed as carrier materials in the compositionand purified water for irrigation (56.58 g for naloxone and 28.29 g fornalmefene and naltrexone), and the mixtures fed into a spray-dryeraccording to a general procedure as follows.

Solid ingredients were weighed into a beaker equipped with a magneticstirring bar, dissolved in water and fed into a spray-dryer (ProCepT,Belgium) equipped with an ultrasonic nozzle operating at 25 kHz. Thefeed rate of the spray-dryer was set at 3.0 g/minute, the inlettemperature was set at 180° C., the gas flow was set at 300 L/min, andthe cyclone gas was set at 1.5 bar.

The resultant spray-dried powder was collected and packed into devicessuitable for nasal powder administration (single shot nasal unidosedevice for disposable use; UDS Monopowder, Aptar Pharma, France), with afill weight of 23 mg. (For naloxone, this constituted a single dose of 4mg of naloxone (calculated as the HCl salt).)

The devices were placed in heat-sealed aluminum pouches before storagefor 6 months at 40° C. and 75% relative humidity (RH).

The chemical composition of the spray-dried mixtures after storage, andthe amount of powder emitted from the devices after actuation, weredetermined.

The stability of naloxone after 6 months (6M), with amounts ofimpurities expressed as a percentage of the related substance (% RS) issummarized for the different saccharides in Table 1 below. Initialvalues of % RS were less than 0.1% for all samples.

TABLE 1 Saccharide Galactose Trehalose Maltitol (Acros (Acros SucraloseSucrose (Roquette, Organics, Organics, (Merck, (Merck, France) BelgiumBelgium Germany) Germany) Stability 6 M 2.44 0.20 0.09 5.40 1.04 (% RS)Emitted dose 2.2 mg 5.3 mg 22.4 mg 4.5 mg 3.8 mg Saccharide IsomaltLactose (BENEO- Mannitol Maltose (Acros Palatinit, (Roquette, (Merck,Organics, Germany) France) Germany) Belgium Stability 1.27 0.99 4.180.07 (% RS) Emitted dose 6.1 mg 21.2 mg 3.9 mg 21.4 mgUnexpectedly, certain monosaccharides, like mannitol, which has beenpreviously used in physical mixtures together with naloxone, provedincompatible when employed in this spray-drying process (in terms of thechemical stability of naloxone). This was to be contrasted withdisaccharides, like lactose, which were generally compatible.

Further, polysaccharides known to have a higher Tg tended to give riseto a higher emitted powder dose. Physical changes as a result of a lowTg gave caking and aggregation of the powder in the devices.

For nalmefene and naltrexone, a similar trend was observed (see Table 2below, where initial % RS values are presented in parentheses).

TABLE 2 API Nalmefene Nalmefene Naltrexone Naltrexone Saccharide LactoseMannitol Lactose Mannitol Stability (% 0.83 (0.77) 1.82 (0.75) 0.33(0.11) 1.12 (0.08) RS) 6M 40/75 Emitted dose 21.7 mg 21.6 mg 20.4 mg19.3 mg

Example 2 Physical Stability of Spray-Dried Powders

In order to assess the physical stability and mitigate the risk forcrystallization during storage, glass transition temperatures (Tg) weredetermined using differential scanning calorimetry (DSC) and arepresented in Table 3 below.

Compositions were prepared generally in accordance with the proceduredescribed in Example 1 above, using mannitol, trehalose and lactose ascarrier materials.

For lactose, the true Tg, as well as that of the formulation subjectedto equilibration at four different RH conditions at 25° C. (10%, 20%,30% and 40% RH), were measured (although 30% was not logged). Formannitol and trehalose, Tg was measured as received (‘Ambient’) andafter drying (‘Dried’).

For the dried samples, the DSC ampoule lid was punched automaticallyimmediately before start of the DSC run, introducing a hole of about 0.3mm diameter. The purpose of this was to allow any remaining moisture toevaporate before the glass transition temperature for a dry formulationwas reached. Hence, this Tg value corresponds to the true Tg withoutinterference from available plasticizers like water.

For the samples equilibrated at different RH values, the DSC lid wasgas-tight throughout the DSC run. Samples were prepared as describedabove.

TABLE 3 Composition RH (%) Tg (° C.) Mannitol Dried — Ambient —Trehalose Dried 119 Ambient 51 Lactose Dried 115 10 60 20 57 30 52 40 36

Using trehalose or lactose as carrier materials gave completelyamorphous compositions, in contrast to mannitol which seemed tocrystalize in the spray-dryer as no Tg could be found and the watercontent was below 1%.

Example 3 Ex-vivo Evaluation of Nasal Mucosal Absorption of Naloxone andNalmefene

A standard static diffusion (Franz) cell set up was employed to set upan ex vivo model for nasal mucosa absorption, using an excised porcinenasal tissue.

Solutions containing naloxone HCl dihydrate, nalmefene HCl, benzalkoniumchloride (Sigma-Aldrich Sweden AB), sucrose monolaurate (IMCD Nordic AB)and/or polysorbate 80 (Croda Nordica AB) were prepared by standardtechniques, to provide formulations according to Table 4 below.Potassium phosphate buffer (Sigma-Aldrich Sweden AB) was added to givethe pH stated in Table 4 below.

TABLE 4 Formulation 1 2 3 4 5 6 7 8 naloxone (mg/mL) 5 5 5 5 5 5 5nalmefene (mg/mL) 5 5 5 5 5 5 5 benzalkonium chloride (mg/mL) 0.1 0.10.1 sucrose monolaurate (mg/mL) 0.4 2 polysorbate 80 (mg/mL) 2 pH 4.54.5 4.5 4.5 4.5 4.5 4.5 6.5Diffusion through the tissue was measured after 7 hours and permeationis shown as mean (three repeats) cumulative transport (μg/cm²; with SD)in FIGS. 8 and 9 for naloxone and nalmefene, respectively.

For both naloxone and nalmefene, slightly higher apparent permeationcoefficients (Papp) were observed in Formulations 7 and 8, whichcontained polysorbate 80 and a higher amount of pH buffer, respectively.No corresponding absorption enhancement was observed in the case ofbenzalkonium chloride or sucrose monolaurate.

Example 4 Naloxone-Containing Composition B

The general procedure described in Example 1 was employed to make aspray-dried composition from naloxone HCl dihydrate (1.199 g), alongwith α-D-lactose monohydrate (5.026 g; DFE Pharma Germany), sucrosemonolaurate D-1216 (0.062 g; Mitsubishi-Kagaku Foods Corporation,Japan).

Composition B comprised a single dose of naloxone of 4 mg (calculated asthe HCl salt).

Devices were placed in heat-sealed aluminum pouches (ProtectivePackaging, UK) before use.

The geometric particle size distribution (PSD) was measured using aMalvern Mastersizer 2000 (Malvern Panalytical Ltd, UK) and aerodynamicparticle size distribution (aPSD) using a fast screening impactor (FSI,Copley Scientific, UK). PSD: d10=15 μm and d90=55 μm, aPSD<5 μm=0%.

General method for PSD measurements: 80 to 100 mg of sample wasdispersed in 5 mL of silicone oil and mixed well before sonication for20 to 30 seconds. Three measurements were made on the solution using aMalvern Mastersizer 2000 (Malvern Panalytical Ltd., UK).

General method for aPSD measurements: A loaded device was actuated in afast screening impactor (FSI, Copley Scientific, UK) fitted with asuitable adaptor, an expansion bulb and a 10 micron insert. Flow wasadjusted to 30±0.5 L/min. Results were reported as fine particle mass(FPM) as % recovered in the filter stage (<5 μm).

Example 5 Naloxone-Containing Compositions A, C and D

The same general procedure as that described in Example 4 above wasfollowed to prepare three further spray-dried powders, with compositionsaccording to Table 5 below.

TABLE 5 Component Quantity per batch (g) Naloxone-Containing CompositionA Naloxone HCl dihydrate 1.199 α-D-Lactose Monohydrate 5.088 Water forirrigation 56.580 Total 62.867 Naloxone-Containing Composition CNaloxone HCl dihydrate 1.199 α-D-Lactose Monohydrate 4.469 Kollidon 30(BASF, Germany) 0.619 Water for irrigation 56.580 Total 62.867Naloxone-Containing Composition D Naloxone HCl dihydrate 2.398α-D-Lactose Monohydrate 3.889 Water for irrigation 56.580 Total 62.867

Compositions A and C comprised single doses of naloxone of 4 mg, andComposition D comprised a single dose of naloxone of 8 mg (eachcalculated as the HCl salt). PSD and aPSD were analyzed using thegeneral method in Example 4 above (see Table 6 below for results).

TABLE 6 Composition A C D d10 (μm) 15 17 17 d90 (μm) 44 57 58 % <5 μm 00 0

Example 6 Intranasally-Administered Naloxone—Pharmacokinetic Study(Healthy Volunteers)

A Phase I clinical study was performed to determine the bioavailabilityof the four investigational naloxone nasal powder formulations (obtainedas described in Examples 4 and 5 above) relative to the referencecommercial product NARCAN® nasal spray (‘Ref’, naloxone hydrochlorideliquid nasal spray, 4 mg; Adapt Pharma, Inc., Radnor, PA, USA).

The study was a single-centre, open label, randomised, single dose5-treatment crossover, relative bioavailability study in healthysubjects. Each subject received each of the four naloxone-containingpowders (Compositions A to D), as well as Ref in a sequence according toa pre-set randomisation schedule, separated by a minimum 24 hourswashout.

Subjects were randomised immediately before administration of the firstdose of investigational medicinal product (IMP) or Ref (if used). Acomputer-generated randomisation schedule was used to allocate subjectnumbers to 1 of 10 treatment sequences (according to a balanced Williamsdesign) with 2 subjects receiving each treatment sequence.

48 subjects were screened for inclusion in the study up to 28 daysbefore dosing. 21 eligible subjects (healthy male and non-pregnant,non-lactating, female subjects between 18 and 55 years of age with abody mass index between 18.0 and 32.0 kg/m²) were admitted to theclinical unit on the evening prior to IMP administration (Day −1) andremained on site until being discharge at 24 hours post-final dose(after receiving all 5 treatments).

Subjects received IMP or Ref in the morning of Days 1, 2, 3, 4 and 5,with an appropriate interval between subjects based on logisticalrequirements (approximately 10 minutes). IMP was administered toalternate nostrils on each day of dosing, starting with the left nostrilon Day 1. A follow-up phone call took place 3 to 5 days after the finaldose to ensure the ongoing wellbeing of the subjects.

Of the 21 subjects that were enrolled, all received IMP. For analysispurposes, all 21 subjects were included in the safety population, safetyanalysis dataset and the PK population. 1 profile was excluded from thePK analysis dataset owing to a dosing failure, such that 20 subjectscompleted the study and were included in the PK analysis dataset.

Plasma concentrations of naloxone were analysed using non-compartmentalanalysis methods to obtain estimates of standard PK parameters as setout below:

Parameter Definition AUC(0-t) area under the curve from 0 time to thelast measurable concentration AUC(0-inf) area under the curve from 0time extrapolated to infinity AUCextrap percentage of AUC(0-inf)extrapolated beyond the last measurable concentration Cmax maximumobserved concentration Tlag Time to the first measurable concentrationTmax Time of maximum observed concentration Lambda-z slope of theapparent elimination phase T½ apparent elimination half-life AUC(0-4min) area under the curve from 0 time to 4 min (0.067 h) post-doseAUC(0-10 min) area under the curve from 0 time to 10 min (0.17 h)post-dose AUC(0-30 min) area under the curve from 0 time to 30 min (0.5h) post-doseThe evaluation of safety parameters comprised analysis of adverse events(AEs), intranasal tolerability, laboratory evaluations, vital signs,electrocardiogram (ECG) and physical examination findings.

Log-transformed exposure parameters (AUCs and Cmax) were compared withstandard methods to assess relative bioavailability using SAS Softwareprocedure PROC MIXED. A single mixed effects model was fitted for eachparameter to obtain estimates of geometric mean ratios (GMRs) andcorresponding confidence intervals (CIs) for all treatment comparisonsof interest. Models included terms for actual treatment received, studyday (i.e. period) and planned sequence fitted as fixed effects andsubject within sequence fitted as a random effect. Results werepresented back-transformed to the linear scale. The followingcomparisons were of interest:

-   -   Relative bioavailability compared to Ref: IMP:Ref GMRs for        AUC(0-t), AUC(0-inf) and Cmax were determined    -   Early exposure compared to Ref: IMP:Ref GMRs for AUC(0 0-4 min),        AUC(0-10 min) and AUC(0-30 min) were determined    -   Dose proportionality of IMD formulations: 8 mg:4 mg GMRs for        AUC(0-t), AUC(0-inf) and Cmax were determined and dose        normalized.

Results

Arithmetic mean naloxone plasma concentrations vs time, by treatment(linear scale) are shown in FIGS. 10 and 11 (first five hours and firsthour after administration, respectively) and are described in Table 7below. Geometric mean naloxone plasma concentrations vs time, bytreatment (semi log scale) are described in Table 7 below.

TABLE 7 Composition A B C D Ref N 19 20 20 20 20 AUC(0-t) 10.7 14.7 10.916.9 7.99 (ng · h/mL)^(a) (24.8) (18.5) (27.6) (35.9) (44.1) AUC(0-inf)10.8 14.8 11.1 17.1 8.06 (ng · h/mL)^(a) (25.3) (18.6) (28.7) (35.9)(44.6) [n = 18] [n = 18] [n = 18] [n = 19] AUCextrap 0.955 0.688 1.2540.865 1.240 (%)^(a) (50.5) (43.9) (79.7) (106.0) (58.0) [n = 18] [n =18] [n = 18] [n = 19] Cmax 8.43 15.6 8.94 12.1 5.67 (ng/mL)^(a) (44.2)(46.5) (35.4) (45.4) (55.8) Tlag 0.000 0.000 0.000 0.000 0.000 (h)^(b) (0.00-0.033) (0.00-0.00)  (0.00-0.034)  (0.00-0.034)  (0.00-0.035) Tmax0.3333 0.2500 0.2500 0.3333 0.3333 (h)^(b) (0.108-0.667) (0.117-0.500)(0.118-0.500) (0.167-0.667) (0.117-0.502) Lambda-z 0.59019 0.570660.53326 0.50483 0.52148 (1/h)^(c) (20.9) (20.6) (31.7) (20.0) (24.7) [n= 18] [n = 18] [n = 18] [n = 19] T½ 1.243 1.269 1.471 1.425 1.404(h)^(c) (30.0) (22.8) (43.6) (20.0) (23.2) [n = 18] [n = 18] [n = 18] [n= 19] N: number of subjects in the dataset; n: number of subjects withan observation. ^(a)Geometric mean (geometric CV %); ^(b)Median (range);^(c)Arithmetic mean (arithmetic CV %)

The analysis of relative bioavailability (GMR, 90% CI) is shown in Table8 below.

TABLE 8 Comparison AUC(0-t) (%) AUC(0-inf) (%) Cmax (%) A: Ref 136.23135.47 149.56 (122.64, 151.33) (121.33, 151.26) (125.75, 177.87) B: Ref184.47 183.89 274.68 (166.36, 204.55) (165.28, 204.60) (231.63, 325.74)C: Ref 136.37 136.91 157.57 (122.99, 151.22) (122.58, 152.92) (132.88,186.86) D: Ref 211.37 213.61 213.07 (190.62, 234.38) (191.25, 238.58)(179.68, 252.67)

All IMPs displayed significantly higher overall and peak plasma exposureof naloxone than Ref. Composition B displayed the highest relativebioavailability of the 4 mg formulations, with approximately 84% higherAUC and 175% higher Cmax than Ref on average (noting that formulation Dincluded 8 mg naloxone hydrochloride, double the amount in the otherformulations). The IMPs, A, B, C and D, also displayed lowerinterpatient variability (CV) in overall and peak exposure parametersthan Ref (see Table 7).

Tables 9 and 10 below shows descriptive statistics of naloxone partialAUCs (as geometric means; geometric CV %) by treatment, on an absolute(Table 9) and relative (Table 10) basis.

TABLE 9 Composition A B C D Ref AUC(0-4 min) 0.0412 0.0895 0.0469 0.05430.0238 (ng · h/mL)^(a) (149.1) (175.4) (159.6) (262.7) (186.5) AUC(0-10min) 0.450 0.991 0.479 0.550 0.267 (ng · h/mL)^(a) (90.7) (87.8) (90.2)(104.9) (103.7) AUC(0-30 min) 2.70 4.82 2.89 3.86 1.88 (ng · h/mL)^(a)(46.1) (42.9) (43.6) (52.3) (60.8)

TABLE 10 AUC(0-4 min) AUC(0-10 min) AUC(0-30 min) AUC(0-t) Comparison(%) (%) (%) (%) A: Ref 174.56 167.04 144.29 136.23 (109.45, 278.41)(122.05, 228.59) (120.63, 172.59) (122.64, 151.33) B: Ref 376.43 370.69256.89 184.47 (237.87, 595.70) (272.29, 504.64) (215.41, 306.36)(166.36, 204.55) C: Ref 197.03 179.25 153.80 136.37 (124.51, 311.80)(131.67, 244.03) (128.96, 183.41) (122.99, 151.22) D: Ref 228.33 205.89205.54 211.37 (144.28, 361.33) (151.24, 280.30) (172.35, 245.12)(190.62, 234.38)All IMPs displayed significantly higher plasma exposure of naloxone thanRef over the first 4, 10 and 30 minutes after dosing. For Composition B,early partial AUC GMRs were much higher than the corresponding AUC(0-t)GMR for this IMP, which is indicative of a higher initial rate ofabsorption from this formulation than with Ref.

Analysis of dose proportionality of IMPs as dose normalised GMRs (90%CI; 8 mg:4 mg; D:A) are shown in Table 11 below.

TABLE 11 Comparison AUC(0-t) (%) AUC(0-inf) (%) Cmax (%) D: A 77.5878.84 71.23 (69.84, 86.17) (70.46, 88.21) (59.90, 84.72)For the scaled point estimates of D:A GMRs for AUC(0-t), AUC(0-inf) andCmax, the 90% CIs lie entirely below 100%.

All IMPs demonstrated significantly higher naloxone exposure than Ref.Compositions A, B, C and D displayed approximately 36%, 84%, 37% and112% higher overall exposure, respectively, relative to Ref, with peakexposure (Cmax) being 50%, 175%, 58% and 113% higher on average,respectively (again noting that Composition D contained 8 mg naloxonehydrochloride, which is double the amount of the other compositions.)

Inter-subject variability in the overall exposure parameters AUC(0-t),AUC(0-inf) and Cmax was lower following administration of CompositionsA, B, C and D compared to Ref.

As can be seen clearly from FIG. 10 and, more clearly from FIG. 11 ,rapid absorption of all formulations, with median Tmax values between0.250 h and 0.333 h, was observed. Early exposure (in terms of AUC(0-4min), AUC(0-10 min) and AUC(0-30 min)) was higher from all IMPs thanthat from Ref. Absorption was most rapid from Composition B, with pointestimates indicative of >270% higher exposure than Ref during the first10 min after dosing. This is a remarkable and completely unexpectedresult, for all of the reasons described hereinbefore.

Elimination of naloxone was similar between all formulations, witharithmetic mean terminal T1/2 values between 1.243 and 1.471 hours.

Nasal administration of naloxone nasal powder at all doses wasconsidered to be safe and well tolerated under the conditions of thetrial.

There were no SAEs, severe AEs or AEs leading to subject withdrawalreported in this study, and the AE profiles were similar to previousstudies of the reference nasal spray in healthy subjects. The mostcommonly reported AEs were nasal inflammation, headache and dizziness.All AEs were mild in severity and, overall, the safety profile of theIMPs corresponded well with previous experience of naloxone HCl inhealthy subjects and there were no findings that raised any safetyconcerns.

Example 7 Physical Stability of Spray-Dried Powders Containing Dextrins

The general procedure as described in Example 1 above was employed tomake two formulations with the following compositions (percentages areby weight of the total composition):

Composition X

Naloxone HCl (35%), 2-hydroxypropyl-β-cyclodextrin (Cavasol W7, HPPharma, Wacker, Germany; 53%), lactose (Merck, Germany; 10%) and Tween20 (Croda Nordica AB, Sweden; 1%)

Composition Y

Naloxone HCl (17%), maltodextrin (Glucidex IT 12 DE, Roquette, France;72%), lactose (10%), sucrose monolaurate (1%).

A similar experiment to that described in Example 2 above was set upmeasuring physical stabilities of Compositions X and Y at different RHvalues, as Tg values. The results are show in Table 12 below.

TABLE 12 Composition RH (%) Tg (° C.) X Dried 152 11 128/97 22 108/78 33 96/— 43  81/52 Y Dried 158/— 11 156/97 22 142/85 33 128/70 43 107/51Both dextrins increased Tg compared to compositions comprising onlylactose as carrier material, facilitating acceptable emitted dose evenafter 24-72 hours of storage at 80° C. The multiple Tg values presentedin Table 10 indicates that the relevant compositions were not fullyhomogeneous, but rather regions with an increased concentration ofhigher molecular weight polysaccharide that are separate from regions oflower molecular weight compounds.

Subsequently-conducted dissolution tests also showed that highconcentrations of maltodextrin did not affect the dissolution ofnaloxone.

Example 8 Chemical Stability of Spray-Dried Powders Containing Dextrins

In order to explore the chemical stability of naloxone as an effect ofdextrins and lactose/dextrin mixtures, samples were prepared using thegeneral procedure as described in Example 1 above. Compositions(percentages are by weight of the total composition) are provided inTable 13.

The chemical stability of naloxone after 3 and 6 months at 40° C./75%RH, with amounts of impurities expressed as a percentage of the relatedsubstance (% RS) is summarized for the different compositions in Table13 below. All initial % RS values were less than 0.1%.

TABLE 13 Composition 3M 6M Naloxone HCl (17%) 0.38 (0.10) 0.07 (0.04)Lactose (83%) Naloxone HCl (17%) 0.34 (0.09) 0.19 (0.06) Lactose (82%)Sucrose monolaurate (1%) Naloxone HCl (17%) 0.75 (0.62) 3.40 (3.40)2-hydroxypropyl-β-cyclodextrin (82%) Sucrose monolaurate (1%) NaloxoneHCl (17%) 0.09 (0.06) 0.24 (0.21) 2-hydroxypropyl-β-cyclodextrin (58%)Lactose (24%) Sucrose monolaurate (1%) Naloxone HCl (35%) 0.45 (0.42)3.05 (3.05) 2-hydroxypropyl-β-cyclodextrin (64%) Sucrose monolaurate(1%) Naloxone HCl (35%) 0.12 (0.09) 0.71 (0.68)2-hydroxypropyl-β-cyclodextrin (45%) Lactose (19%) Sucrose monolaurate(1%) Naloxone HCl (17%) 0.39 (0.24) 0.29 (0.29) Maltodextrin 12DE (82%)Sucrose monolaurate (1%) Naloxone HCl (17%) 0.12 (0.05) 0.05 (0.05)Maltodextrin 12DE (63%) Lactose (19%) Sucrose monolaurate (1%) NaloxoneHCl (35%) 0.29 (0.29) 0.28 (0.28) Maltodextrin 12DE (64%) Sucrosemonolaurate (1%) Naloxone HCl (35%) 0.13 (0.10) 0.11 (0.08) Maltodextrin12DE (45%) Lactose (19%) Sucrose monolaurate (1%)The numbers in brackets in Table 13 are the % RS taking away that valuemeasured for Impurity E (Imp E), which is a documented impurity relatedto naloxone (dimer). In this study, Imp E seems to be formed duringsample preparation prior to analysis, which affects the total % RS valuein an uncontrolled way and prevents the detection of minor degradationtrends.

It is clear from Table 13 that dextrins unexpectedly inducedecomposition of naloxone, but that the addition of lactose mitigatesthis effect.

Example 9 Nalmefene-Containing Compositions E, F and G

The same general procedure essentially as described in Examples 1 and/or4 above was followed to prepare three nalmefene-containing spray-driedpowders, with compositions according to Table 14 below. In this and thenext example, nalmefene was sourced from Mallinckrodt Inc., USA.

TABLE 14 Component Quantity per batch (g) Nalmefene-ContainingComposition E Nalmefene HCl 3.106 α-D-Lactose Monohydrate 18.162 Sucrosemonolaurate 0.206 Water for irrigation 193.257 Total 214.731Nalmefene-Containing Composition F Nalmefene HCl 3.004 α-D-LactoseMonohydrate 4.188 Maltodextrin 12DE 12.713 Sucrose monolaurate 0.199Water for irrigation 178.852 Total 198.956 Nalmefene-ContainingComposition G Nalmefene HCl 3.284 α-D-Lactose Monohydrate 9.158Maltodextrin 12DE 31.298 Sucrose monolaurate 0.218 Water for irrigation395.620 Total 439.578Compositions E and F comprised single doses of nalmefene of 3 mg, andComposition G comprised a single dose of nalmefene of 3 mg, but at halfconcentration and double fill weight (each calculated as the free base).PSD and aPSD were analyzed using the general method in Example 4 above(see Table 15 below for results).

TABLE 15 Composition E F G d10 (μm) 18 20 19 d90 (μm) 51 66 65 % <5 μm 00 0

Using the method described in Example 2 above, all of the compositionsexhibited a glass transition at around 60° C., in ambient conditions.However, Composition E produced a large crystallisation event at justabove 100° C., which was not seen in the maltodextrin-containingCompositions F and G. In addition, Composition E underwentcrystallization at room temperature in 60% RH, something that was notseen in Compositions F and G.

Example 10 Chemical Stability of Spray-Dried Powders ContainingNalmefene

Samples were prepared using the general procedure essentially asdescribed in Examples 1 and/or 4 above. Compositions (percentages are byweight of the total composition) are provided in Table 16 below.

The chemical stability of nalmefene 3 and 6 months at 40° C./75% RH,with amounts of impurities expressed as a percentage of the relatedsubstance (% RS) is summarized for the different compositions in Table16 below. All initial % RS values were less than 0.1%.

TABLE 16 Composition 3M 6M Nalmefene HCl (15%, 0.45 g) 0.14 0.05 Lactose(84%) Sucrose monolaurate (1%) Nalmefene HCl (15%, 0.45 g) 0.10 0.00Maltodextrin 12DE (64%) Lactose (20%) Sucrose monolaurate (1%) NalmefeneHCl (15%, 0.45 g) 0.11 0.07 Maltodextrin 12DE (74%) Lactose (10%)Sucrose monolaurate (1%) Nalmefene HCl (7.5%, 0.225 g) 0.16 0.00Maltodextrin 12DE (71.5%) Lactose (20%) Sucrose monolaurate (1%)

The invention claimed is:
 1. A solid pharmaceutical composition in theform of a spray-dried powder comprising: a pharmacologically-effectiveamount of naloxone or a pharmaceutically-acceptable salt thereof; and apharmaceutically-acceptable carrier material comprising a combinationof: (i) a disaccharide selected from the group consisting of maltitol,trehalose, sucralose, sucrose, isomalt, maltose, and lactose; and (ii) adextrin; wherein the composition is essentially free of water and issuitable for nasal delivery of naloxone or thepharmaceutically-acceptable salt thereof, and the naloxone orpharmaceutically-acceptable salt thereof is less than about 15%chemically degraded after storage for 3 months at 75% relative humidityand 40° C.
 2. The composition as claimed in claim 1, wherein the lowestmeasurable glass transition temperature of the composition is at leastabout 40° C. when measured at a relative humidity of about 35%.
 3. Thecomposition as claimed in claim 1, wherein the particle sizedistribution of the spray-dried powder includes a Dv(10) that is aboveabout 3 μm.
 4. The composition as claimed in claim 1, wherein thedisaccharide comprises lactose and/or trehalose.
 5. The composition asclaimed in claim 1, which further comprises an alkyl saccharide.
 6. Thecomposition as claimed in claim 5 wherein the alkyl saccharide comprisesa sucrose ester.
 7. The composition as claimed in claim 6, wherein thesucrose ester comprises sucrose monolaurate.
 8. The composition asclaimed in claim 1, wherein the dextrin comprises a cyclodextrin or amaltodextrin.
 9. The composition as claimed in claim 1, wherein thecarrier material comprises α-D-lactose monohydrate as the disaccharideand one or more of 2-hydroxypropyl-β-cyclodextrin and/or maltodextrin12DE as the dextrin.
 10. The composition as claimed in claim 1, whereinthe dextrin comprises a maltodextrin.
 11. The composition as claimed inclaim 10, wherein the carrier material comprises α-D-lactose as thedisaccharide, and a maltodextrin.
 12. The composition as claimed inclaim 1, wherein the disaccharide is present in an amount of betweenabout 10% and about 30% by weight based on the total weight of thecomposition.
 13. The composition as claimed in claim 1, wherein theratio of disaccharide:dextrin is between about 10:1 and about 1:10 byweight based on the total weight of the composition.
 14. The compositionas claimed in claim 1, wherein the powder has a particle sizedistribution that includes a volume-based mean diameter within the rangeof about 10 μm and about 100 μm.
 15. A process for the manufacturing ofa pharmaceutical composition as defined in claim 1, wherein said processcomprises the steps of: (a) mixing together in a volatile solvent,naloxone, or a pharmaceutically-acceptable salts thereof, andpharmaceutically-acceptable carrier materials comprise a combination of:and (b) spray-drying the mixture from step (a) to form thepharmaceutical composition comprising spray-dried particles.
 16. Acomposition obtainable by the process as defined in claim
 15. 17. Anasal applicator device suitable and/or adapted for delivery of thepharmaceutical composition as defined in claim 1 to the nose, whichcomprises, or is adjunct and/or attached to, a reservoir, within whichreservoir said composition is contained.
 18. A process for themanufacturing of the applicator device as claimed in claim 17, theprocess comprising the steps of: i) mixing together naloxone or saltthereof and the pharmaceutically-acceptable carrier materials in avolatile solvent; ii) spray-drying the mixture from step i) to form thepharmaceutical composition comprising spray-dried particles; and iii)loading the pharmaceutical composition formed in step ii) into thereservoir within or adjunct or attached to said applicator device.
 19. Amethod of treating opioid overdose, which method comprises administeringthe composition as defined in claim 1 to a subject in need of suchtreatment.
 20. The method as claimed in claim 19, wherein thecomposition is administered to said subject by way of an applicator thatcomprises, or is adjunct and/or attached to, a reservoir, within whichreservoir said composition is contained.
 21. The composition as claimedin claim 1, which comprises less than about 5% of water.
 22. Thecomposition as claimed in claim 1, which comprises less than about 2% ofwater.
 23. The composition as claimed in claim 1, which comprises lessthan about 1% of water.
 24. The nasal applicator device as claimed inclaim 17, which is packaged within a container that substantiallyprevents the ingress of atmospheric water under the storage conditionsof 75% relative humidity and 40° C.
 25. The nasal applicator device asclaimed in claim 17, which is packaged within a container that comprisesa material selected from the group of heat-sealed aluminum pouches andthermoformed plastics.
 26. A process for the manufacturing of anapplicator device as claimed in claim 24, the process comprising: i)mixing together naloxone or salt thereof and thepharmaceutically-acceptable carrier materials in a volatile solvent; ii)spray-drying the mixture from step i) to form the pharmaceuticalcomposition comprising spray-dried particles; iii) loading thepharmaceutical composition formed in step ii) into the reservoir withinor adjunct or attached to said applicator device; and iv) loading theapplicator device from step iii) into the container that substantiallyprevents the ingress of atmospheric water.
 27. A process for themanufacturing of an applicator device as claimed in claim 25, theprocess comprising: i) mixing together naloxone or salt thereof and thepharmaceutically-acceptable carrier materials in a volatile solvent; ii)spray-drying the mixture from step i) to form the pharmaceuticalcomposition comprising spray-dried particles; iii) loading thepharmaceutical composition formed in step ii) into the reservoir withinor adjunct or attached to said applicator device; and iv) loading theapplicator device from step iii) into the container that comprises amaterial selected from the group of heat-sealed aluminum pouches andthermoformed plastics.
 28. The composition as claimed in claim 1,wherein the naloxone or pharmaceutically-acceptable salt thereof is lessthan about 10% chemically degraded after storage for 3 months at 75%relative humidity and 40° C.
 29. A nasal applicator device suitableand/or adapted for delivery of the composition as defined in claim 28 tothe nose, which comprises, or is adjunct and/or attached to, areservoir, within which reservoir said composition is contained.
 30. Thenasal applicator device as claimed in claim 29, which is packaged withina container that substantially prevents the ingress of atmospheric waterunder the storage conditions of 75% relative humidity and 40° C.
 31. Thenasal applicator device as claimed in claim 29, which is packaged withina container that comprises a material selected from the group ofheat-sealed aluminum pouches and thermoformed plastics.
 32. Thecomposition as claimed in claim 1, wherein the naloxone orpharmaceutically-acceptable salt thereof is less than about 5%chemically degraded after storage for 3 months at 75% relative humidityand 40° C.
 33. A nasal applicator device suitable and/or adapted fordelivery of the composition as defined in claim 32 to the nose, whichcomprises, or is adjunct and/or attached to, a reservoir, within whichreservoir said composition is contained.
 34. The nasal applicator deviceas claimed in claim 33, which is packaged within a container thatsubstantially prevents the ingress of atmospheric water under thestorage conditions of 75% relative humidity and 40° C.
 35. The nasalapplicator device as claimed in claim 33, which is packaged within acontainer that comprises a material selected from the group ofheat-sealed aluminum pouches and thermoformed plastics.